ETHICAL ISSUES IN TISSUE ENGINEERING EUROPEAN ETHICAL - LEGAL PAPERS N°7

ETHICAL ISSUES IN TISSUE ENGINEERING

Leen Trommelmans Joseph Selling Kris Dierickx

EUROPEAN ETHICAL - LEGAL PAPERS N° 7

© Kris Dierickx and Herman Nys Preferred citation: L. TROMMELMANS, et al., “Ethical issues in Tissue Engineering”, European Ethical-Legal Papers N°7, Leuven, 2007. All rights reserved

ISBN: xxxxx

FOREWORD

Within the Centre for Biomedical Ethics and Law of the Catholic University of Leuven - one of the leading bioethical and legal research centres in Europe - we are involved as coordinator, partner or participant in different European research projects. Biomedical ethics and law are rapidly evolving disciplines. Although there exists already a great number of specialised peer reviewed journals and series of books in both disciplines we felt a growing need for a medium through which the results of our research can directly be presented to the research community and the interested community at large. To meet this need we decided to start the European Ethical-Legal Papers. Such papers will also contribute to the transparency we owe to society that finances our research efforts. We also hope that it will contribute to the discussion and the exchange of information and ideas among researchers in Europe and elsewhere.

Herman NYS Professor Medical Law

Kris DIERICKX Associate Professor Medical Ethics

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TABLE OF CONTENT

I.

Introduction..................................................................................1

II.

What is Tissue Engineering..........................................................3 § 1. The tissue engineering process ..............................................3 A. Complexity............................................................4 B. Continuity .............................................................5 §2. Future of TE ...........................................................................6

III. Legal and ethical frameworks for TE research and application in the European Union .................................................................9 §1. Legal framework ....................................................................9 A. Introduction...........................................................9 B. Directives relevant to the development, production and use of HTEPs ............................10 C. Conclusion ..........................................................14 § 2. Ethical framework...............................................................15 A. Introduction.........................................................15 B. Ethical documents and texts relevant to the development, production and use of HTEPs......16 C. Conclusion ..........................................................46 IV.

Ethical questions for HTEPs and TE .........................................49 § 1. Introduction: four approaches to TE and HTEPs in Europe and the ethical issues they raise...............................49 § 2. Anthropological issues.........................................................50

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A. B. C.

Interpretation of the meaning of the human body....................................................................51 Changes in the life cycle. ....................................51 Exchange of human material...............................52

§ 3. Socio-economic approach ...................................................53 A. Access to HTEPs.................................................53 B. Organization of health care systems ...................57 § 4. HTEPs as examples of regenerative medicine....................58 A. The interests of the donor of the cells .................59 B. Importance and place of animal and clinical trials....................................................................61 C. Conduct of clinical trials .....................................62 D. Post-trial events...................................................66 § 5. Specific HTEPs and applications........................................67 A. Niche of HTEPs ..................................................67 B. Composition of the HTEP: specific cells and materials .............................................................68 C. Applications for life threatening conditions........71 D. Specific applications: pediatric applications.......71 § 6. Final note: hype and hope ...................................................72 V.

Concluding Remarks..................................................................74

VI.

Bibliography .............................................................................79

Already published ...............................................................................82

III

I.

INTRODUCTION

Tissue engineering (TE) is a relatively new development in medicine. It is the generation, in vitro, of human tissue for clinical applications, based on human cells. The aim of TE is to regenerate the body and to restore it to full physiological activity through the implantation of human tissue engineered products (HTEPs). Tissue engineered skin and cartilage implants for the knee have been applied successfully, while other HTEPs such as bladder, heart valves, and heart muscle are being developed. The main targets for the application of HTEPs today are degenerating or irreparably damaged tissues (Fodor, 2003). Diseases due to the degeneration of tissues or organs are increasingly common in an ageing European population; therefore the therapeutic benefits of TE promise to be considerable. The demand for these products may increase significantly. However, the advance of TE has been slow due to scientific and technical difficulties and because of regulatory, economic and ethical challenges (Williams, 2006a). New developments in science and medicine are increasingly subject to intense ethical scrutiny. Throughout Europe various stakeholders present a wide variety of philosophical, religious and economic viewpoints that influence their position in the ethical debate. TE is assessed with regard to the impact it may have on principles, norms and views that these stakeholders hold dear. The outcome of this debate will influence the development of TE in general or of specific HTEPs, the conditions for its acceptance or the grounds for its rejection. This European Ethical-Legal Paper provides an overview of the ethical issues related to TE. In the first chapter we give a short description of TE as a new medical technology. In a second chapter we provide an overview of the relevant European regulatory and ethical frameworks and the fundamental ethical principles they put forward for biomedical research and therapy, including the development and use of HTEPs. We have restricted our survey of the ethical and legal documents to documents issued by the European

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Union, the Council of Europe and the European Group on Ethics. Guidance and regulations are also being developed outside the EU. These documents provide useful information, but we have opted not to include them in this paper. In a third chapter we concentrate on four approaches to the ethical evaluation of TE and HTEPs and investigate the ethical questions that each of these four fields raises with respect to TE and HTEPs. These fields are: (1) the anthropological perspective, (2) social and economic concerns, (3) HTEPs and TE as examples of regenerative medicine and (4) the development of specific HTEPs. We have chosen this approach in order to make the discussion more transparent, although we are aware that these four fields influence each other, and that this methodology has some limitations. We are also aware that TE is rapidly developing and that many of the ethical concerns can not yet be fully envisioned. The aim of this European Ethical-Legal Paper therefore is not to provide comprehensive guidelines for the ethically responsible conduct of TE research and the use of HTEPs in therapy, but to give a first overview of the relevant ethical questions. We hope that this publication will stimulate the discussion. Therefore we welcome all reactions at [email protected] A special word of thanks to prof.dr. Herman Nys and to prof.dr. Frank Luyten for their valuable comments on this subject and to Tom Goffin who provided the lay-out for this European Ethical-Legal Paper. Leuven, 31 May, 2007 The research for this publication was supported by the STEPS project of the EU, FP6-500465. www.stepsproject.com

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II. WHAT IS TISSUE ENGINEERING § 1. The tissue engineering process Tissue engineering is ‘the creation of new tissue for the therapeutic reconstruction of the human body, by the deliberate and controlled stimulation of selected target cells, through a systematic combination of molecular and mechanical signals’ (Williams, 2006a). The in vitro combination of donated, cultured and altered human cells with supporting structures and biomolecules yields metabolically active constructs: HTEPs. Fig.1 gives an overview of the TE process in general. Scientists argue that TE is part of the new field of regenerative medicine which also includes gene therapy and somatic cell therapy (Lavik and Langer, 2004; Fodor, 2003). The aim of regenerative medicine is to induce regeneration of the body and not merely to restore a particular function of the tissue. Once implanted, HTEPs generate an interaction with the body, enabling it to replace damaged or degenerated tissue, to integrate the HTEP into the body, and to achieve regeneration of the tissue. This interaction is desired but it has to be guided cautiously in order to gain full incorporation of the product and to regain and retain full functionality of the body, without generating inflammation, unwanted cell growth, rejection, or long term adverse events, (European Commission, SANCO, 2001).

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Human cells

Cell manipulation

Cell expansion

Animal trial

Combination with extracellular matrix and biomolecules

Clinical trial

Therapy

Exposure to stress

Human Tissue Engineered Product

Packaging and transport/ control

Cell sourcing

HTEP production

Trials

Application

Figure 1: tissue engineering process

TE however has a defining characteristic that sets it apart from gene therapy and somatic cell therapy. In TE a complex and metabolically active structure is created in vitro before it is implanted in the body. This characteristic gives TE two crucial features: (1) it is a complex process that is conducted partly in vitro and partly in vivo. (2) It is a continuous process in which the HTEP interacts with its environment and changes over time. A.

Complexity

Three factors contribute to the complexity of TE. (1) All HTEPs show a certain amount of variability because they contain metabolically

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active cells in the dynamic environment of the extracellular scaffolds (2) Implanting the HTEP initiates an ongoing interaction between the HTEP and the recipient’s body which also varies to some extent. These two features make standardisation of TE processes difficult and increase the amount of (unforeseeable) risks. (3) Implanting a HTEP is an irreversible process: once the process of integration and regeneration is initiated it is impossible to reverse it completely. As a result of this complexity a large number of variables and interactions have to be taken into account at every step of the in vitro development of the HTEP, and during the process of regeneration in vivo. Every step of the process must therefore be carefully monitored, especially with regard to safety issues and the assessment of risks and benefits, before proceeding to the next step. These are not purely technical matters; they also have a strong ethical component: participants in clinical trials and patients need to be protected against unjustifiable risks. In a process as complex as TE, risk assessment needs to be rigorously conducted and the anticipated risks balanced against potential benefits on the one hand; and compared with the risks and benefits of existing therapies on the other hand. One does not only have to take the safety of the HTEP into account, but also its efficacy, especially if other therapies are available whose efficacy has been validated. Even if a HTEP is safe, if it isn’t efficacious while efficacious therapies exist, there are no arguments to introduce them in the patient. The degree of safety and efficacy that is required before starting a trial may be smaller than the required efficacy before entering a product on the market. Yet even for a trial a minimal level of efficacy should be anticipated. B.

Continuity

TE is not a sequence of independent activities; all steps in the process are interdependent. Every link in the chain of events that leads to the application of a particular HTEP codetermines the end result. This implies that we need to consider every single stage of the TE process

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with the entire context of TE in mind, if we want to make an adequate ethical assessment of TE and HTEPs. The choice of specific cells, the construction of scaffolds and the design and culture conditions in the bioreactor, all play a decisive role in the final characteristics of the implantable HTEP and they will influence each other. Information gathered from the clinical trial results and from the post-clinical trial phase can be fed back to the preclinical development stages of the HTEP and lead to an adjustment of the construction of the HTEP and of the culture conditions of the HTEP in order to provide a better adapted HTEP for the application it is intended for. Because of the interdependence of the different phases of TE, from cell sourcing to therapy and long-term follow-up, it is advisable to revise the different elements of the entire TE process in a critical way, and to ask if TE is not in need of specific guidance that takes this continuity into account. Despite the wide variety of potential HTEPs, the continuity and complexity of the process will be common to all HTEPs. We have to acknowledge and explore the implications of these two features of TE in order to come to an ethically acceptable development of this domain.

§ 2. Future of TE Regeneration through TE holds many promises, but has been disappointing so far. One of the reasons for the slow advancement of TE as an art and a craft may stem from the current approach to TE that rests heavily on the engineer’s approach to the design and development of tissues. In order to create safe and robust HTEPs for various applications, TE may benefit greatly from the scientific background provided by developmental biology, which tries to elucidate the fundamental processes that occur in naturally developing tissues and is familiar with these complex and continuous processes. The potential scope for the application of TE and HTEPs is large: every tissue that is prone to degeneration is a candidate for TE.

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However, a number of crucial steps still have to be taken before the promises of TE turn into reality. The HTEPs that have been developed so far (TE-skin, autologous cartilage implants for the knee) are relatively simple products, containing only a very limited number of cell types, not interfering with the circulatory system and not immunologic ally sensitive. They contain cells that do not raise much ethical debate, apart from the questions related to the secondary use of surgically removed tissue. They are not used for life-threatening conditions, and alternative treatments are possible if the HTEP is not efficient or must be removed. Yet even these first tissue engineered products suffer from severe difficulties, both from a technical and scientific point of view (e.g. the upscaling of the production of HTEPs and the transfer of knowledge from one domain to the other), as from an economic and a regulatory point of view. (Williams, 2006a) The HTEPs that are envisioned (e.g. TE arteries, heart muscle) are more complex and possibly derived from undifferentiated stem cells, therefore carrying a larger risk- despite the equally large benefits that may follow their successful application. Complex tissues- and a fortiori organs- are also at a more elevated level of organisation. Before attaining this level of organisation in HTEPs a more profound understanding of the developmental trajectories that lead to these tissues is needed in order to produce safe and reliable HTEPs. These advanced HTEPs may be used for life-threatening conditions and composed of ethically ‘sensitive’ cells such as human embryonic stem cells, or xenogeneic cells. The evolution of TE will consequently give rise to more ethical questions. The ability to successfully regenerate human tissue also raises anthropological questions, and presents new challenges for the organisation of health care in Europe. A complicating factor in this discussion is that some of the ethical questions raised by the development of TE are relevant for all HTEPs, while others will only be relevant for specific HTEPs- with regard to their composition or with regard to their application.

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Because of this complexity many stakeholders are convinced that a profound ethical deliberation with regard to all aspects of TE and HTEPs is necessary.

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II. LEGAL AND ETHICAL FRAMEWORKS FOR TE RESEARCH AND APPLICATION IN THE EUROPEAN UNION §1. Legal framework A.

Introduction

Stakeholders agree that TE and HTEPs are best regulated at the European Level (European Commission, 2005). Several elements of the development and application of HTEPs are already governed by European Directives that function as ‘European framework laws’. Directives adopted by the European Commission and the European Parliament must be incorporated in national law by member states. Directives have primacy over member state law as long as they do not interfere with the subsidiarity principle. An EU regulation concerning Advanced Therapy Medicinal Products, which includes HTEPs, has been voted in the European Parliament (25 April 2007). This regulation should apply one year after entry into force, i.e. around mid-2008. HTEPs are health products and find themselves in an area of tension. They are considered to be tradeable goods and are consequently governed by the European Treaties and Directives. As health related products they are however subject to the authority of the individual member states, due to the principle of subsidiarity for health care matters (art.152, 4(c) of the consolidated version of the Treaty establishing the European Community). The management of the health care system and the use of animal cells and of human embryonic stem cells are examples of issues that are exempt from an EU-wide regulation and belong to the legal authority of the member states. This ‘hybrid’ character of HTEPs will certainly have an influence on the future regulation, development, marketability and application of specific HTEPs.

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B.

Directives relevant to the development, production and use of HTEPs

1.

Regulation concerning the production and marketing of HTEPs

1.1. European Parliament legislative resolution of 25 April 2007 on the proposal for a regulation of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (COM(2005)0567 – C6-0401/2005 – 2005/0227(COD)) http://www.europarl.europa.eu/oeil/file.jsp?id=5291242 Subjects: Subsidiarity, respect for fundamental human rights, marketing authorisation requirements (incl. donation and procurement of cells, testing, clinical trials and GMP), post authorisation requirements (incl. risk management and traceability) Note: as this Regulation is not yet been published in the eur-lex system, we refer the reader to the documents published on the Legislative Observatory website. (May, 2007). 1.2. Commission Staff Working Document. Annex to the proposal for a regulation on advanced therapy medicinal products. Impact assessment (COM (2005) 567 final) http://pharmacos.eudra.org/F2/advtherapies/docs/SEC_2005_1444_EN .pdf Subjects: Subsidiarity, public expenditure, social impacts, information and consent of the donor, free donation and financial benefits by private undertakings, privacy, data protection and traceability, safety, priorities of access, research and clinical trials, use of embryonic stem cells, patenting, monitoring and evaluation of impacts, ex-post evaluation, xenogeneic HTEPs, market authorisation, postauthorisation. 2. Human tissues and cells 2.1. Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells

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http://europa.eu.int/eurlex/pri/en/oj/dat/2004/l_102/l_10220040407en0 0480058.pdf Subjects: obligations of member states, donor selection and evaluation (incl. informed consent, voluntary and unpaid donation), confidentiality, privacy, traceability, quality and safety of donated material. 2.2. Directive 2006/17/EC of 8 February 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells http://europa.eu.int/eurlex/lex/LexUriServ/site/en/oj/2006/l_038/l_03820060209en00400052. pdf Subjects: requirements for the procurement of human tissues and cells, selection criteria for donors, standard operating procedures, privacy, traceability. 3. Medical Devices 3.1. Council Directive 93/42/EEC concerning medical devices, amended by Dir 98/79/EC, Dir. 2000/70/EC and Dir. 2001/104/EC http://www.translate.com/multilingual_standard/MDD.pdf 3.2. Proposal for a Directive of the European Parliament and of the Council on [...] amending Council Directives 90/385/EEC and 93/42/EEC and Directive 98/8/EC of the European Parliament and the Council as regards the review of the medical device directives http://europa.eu.int/comm/enterprise/medical_devices/revision_docs/e ntr-2005-01983-01-00-en.pdf 4. Medicinal products Commission Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use. http://europa.eu.int/eurlex/pri/en/oj/dat/2003/l_159/l_15920030627en00460094.pdf

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Subjects: Analytical, pharmacotoxological and clinical standards and protocols in respect of the testing of medicinal products (Annex I). 5. Good manufacturing and clinical practices 5.1. Commission Directive 2003/94/EC laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use http://europa.eu.int/eurlex/pri/en/oj/dat/2003/l_262/l_26220031014en00220026.pdf 5.2. Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products http://eur-lex.europa.eu/LexUriServ/site/en/oj/ 2005/l_091/l_09120050409en00130019.pdf 6. Patenting Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions http://europa.eu.int/eurlex/pri/en/oj/dat/1998/l_213/l_21319980730en00130021.pdf Subjects: patentability (incl. what is considered to be unpatentable), scope of protection, deposit, access and re-deposit of a biological material 7. Clinical trials Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use

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http://europa.eu/eurlex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf Subjects: Protection of clinical trial participants. Clinical trials on minors/on incapacitated adults unable to give consent. Ethics committees. Commencement of a clinical trial/conduct of a clinical trial. Exchange of information. Suspension of a trial. Manufacture and import of investigational medicinal products. Notification of adverse events/adverse reactions. 8. Privacy 8.1. Directive 2002/58/EC of the European Parliament and of the Council of 12 July 2002 concerning the processing of personal data and the protection of privacy in the electronic communications sector http://europa.eu.int/eurlex/pri/en/oj/dat/2002/l_201/l_20120020731en00370047.pdf Subjects: general rules, security, confidentiality, transfer of personal data to third countries, codes of conduct. 8.2. Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data http://europa.eu.int/eurlex/lex/LexUriServ/LexUriServ.do?uri=CELEX:31995L0046:en:HTM L 9. Traceability Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC http://europa.eu.int/eurlex/pri/en/oj/dat/2003/l_033/l_03320030208en00300040.pdf

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C.

Conclusion

The fundamental principles that are incorporated in these directives that are relevant for the development of HTEPs can be summarised as follows: - Respect for the legislative autonomy of member states with regard to specific health related matters (esp. allowability of certain cell types, their sale and use, definition of criteria for priority access…). - Respect for fundamental human rights as laid down in the Charter of Fundamental Rights of the European Union and the Convention on Human Rights and Biomedicine and its protocols. - Informed consent must be obtained from cell, tissue and organ donors or their representatives prior to the prelevation of the material. - Voluntary and unpaid donation of cells, tissues and organs. - Respect for the privacy, anonymity and confidentiality of the donor. - Protection of the safety of recipients through the testing of the quality of the donated cells, of all the material used during the process, and of the HTEPs. - Protection of the safety of recipients through risk management, good manufacturing and clinical practices, the maintenance of a traceability chain and post-authorisation measures. - Responsible conduct of clinical trials with HTEPs, incl. informed consent and protection of the trial participant. Oversight of clinical trials by ethics committees. - Creation of a regulatory environment that favors the development of HTEPs. - The patentability of biotechnological inventions except if these inventions are contrary to ‘ordre public’ or morality. It is clear that these very general principles need to be translated in appropriate guidelines for TE. We have argued in chapter II that TE has features that require specific attention. Practices and guidelines that have been developed in other areas of medicine can therefore be informative with regard to the development of guidelines for TE, but these existing practices will need to be checked against the reality of TE and if necessary revised in such a way that the fundamental ethical principles that guide research and medicine are upheld and applied in

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this new domain. We will explore these challenges in chapter IV of this European Ethical-Legal Paper.

§ 2. Ethical framework A.

Introduction

Medical research and medical practice are not only governed by the legal framework of European Directives. A body of treaties and conventions has been developed in recent years safeguarding for all European citizens their human rights and fundamental ethical principles in research with human beings or in medical practice. This ethical framework carries substantial weight in the analysis of new biomedical technologies. The most important European agents in the development of this framework are the European Union, the Council of Europe, and the European Group on Ethics. The most relevant documents in this respect are the Charter of Fundamental Rights of the EU, and the Convention on Biomedicine and its protocols which are issued by the Council of Europe. The principles that are laid down in these documents form the background for every deliberation on the ethical issues of TE, even when these treaties and documents are not ratified by all member states of the EU. The impact of the European Charter and of the Biomedicine Convention and its Protocols continually increases as more and more European countries translate the principles in these documents into national legislation for specific biomedical applications. We refer the interested reader to other issues of the European Ethical-Legal Papers. Another important contribution to the establishment of a European ethical framework in biomedicine is made by the European Group on Ethics (EGE). The EGE provides opinions on specific biomedical issues and investigates how general bio-ethical principles of the Charter and the Conventions can be interpreted and applied to these issues.

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These opinions do not have any legal power as such, but they strongly influence the ongoing debates because they can be part of the impact assessment that accompanies every European directive. B.

Ethical documents and texts relevant to the development, production and use of HTEPs

1. European Union Charter of Fundamental Rights of the EU http://www.europarl.eu.int/charter/pdf/text_en.pdf The Charter of Fundamental Rights of the EU is incorporated as part II of the draft Treaty establishing a Constitution for Europe. This constitution is not yet adopted, although the Parliament, Council and Commission signed and proclaimed the Charter on 7 December 2000 in Nice. The following articles have an immediate impact on the development of TE: CHAPTER I: Dignity Article 3: Right to the integrity of the person 1. Everyone has the right to respect for his or her physical and mental integrity. 2. In the fields of medicine and biology, the following must be respected in particular: . the free and informed consent of the person concerned, according to the procedures laid down by law, . the prohibition of eugenic practices, in particular those aiming at the selection of persons, . the prohibition on making the human body and its parts as such a source of financial gain, . the prohibition of the reproductive cloning of human beings. CHAPTER II: Freedoms Article 8: Protection of personal data

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1. Everyone has the right to the protection of personal data concerning him or her. 2. Such data must be processed fairly for specified purposes and on the basis of the consent of the person concerned or some other legitimate basis laid down by law. Everyone has the right of access to data which has been collected concerning him or her, and the right to have it rectified. 3. Compliance with these rules shall be subject to control by an independent authority. CHAPTER IV: Solidarity Article 35: Health care Everyone has the right of access to preventive health care and the right to benefit from medical treatment under the conditions established by national laws and practices. A high level of human health protection shall be ensured in the definition and implementation of all Union policies and activities. 2. Council of Europe 2.1. Convention on Human Rights and Biomedicine a. Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. Oviedo, 4.IV.1997 http://conventions.coe.int/treaty/en/treaties/html/164.htm The ‘Convention on Human Rights and Biomedicine’ and its additional protocols are issued by the Council of Europe. These documents achieve legal status in a member of the Council of Europe when the national government signs and ratifies them. A simplified and updated chart of signatures and ratifications by Member States of the Council of Europe can be found at: http://conventions.coe.int/Treaty/Commun/ListeTableauCourt.asp?MA =9&CM=16&CL=ENG

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The following articles have an immediate impact on the development of TE:

CHAPTER II: Consent Article 5 –General rule An intervention in the health field may only be carried out after the person concerned has given free and informed consent to it. This person shall beforehand be given appropriate information as to the purpose and nature of the intervention as well as on its consequences and risks. The person concerned may freely withdraw consent at any time. Article 6 –Protection of persons not able to consent 1. subject to Articles 17 and 20 below, an intervention may only be carried out on a person who does not have the capacity to consent, for his or her direct benefit. 2. Where, according to law, a minor does not have the capacity to consent to an intervention, the intervention may only be carried out with the authorisation of his or her representative or an authority or a person or body provided for by law. 3. The opinion of the minor shall be taken into consideration as an increasingly determining factor in proportion to his or her age and degree of maturity. 4. Where, according to law, an adult does not have the capacity to consent to an intervention because of a mental disability, a disease or for similar reasons, the intervention may only be carried out with the authorisation of his or her representative or an authority or a person or body provided for by law. The individual concerned shall as far as possible take part in the authorisation procedure. 5. The representative, the authority, the person or the body mentioned in paragraphs 2 and 3 above shall be given, under the same conditions, the information referred to in Article 5. 6. The authorisation referred to in paragraphs 2 and 3 above may be withdrawn at any time in the best interests of the person concerned.

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CHAPTER III –Private life and right to information Article 10 – Private life and right to information 1. Everyone has the right to respect for private life in relation to information about his or her health. 2. Everyone is entitled to know any information collected about his or her health. However, the wishes of individuals not to be so informed shall be observed. 3. In exceptional cases, restrictions may be placed by law on the exercise of the rights contained in paragraph 2 in the interests of the patient. CHAPTER IV –Human genome Article 13 – Interventions on the human genome An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants. CHAPTER V – Scientific research Article 16 – Protection of persons undergoing research Research on a person may only be undertaken if all the following conditions are met: I there is no alternative of comparable effectiveness to research on humans; 2. the risks which may be incurred by that person are not disproportionate to the potential benefits of the research; 3. the research project has been approved by the competent body after independent examination of its scientific merit, including assessment of the importance of the aim of the research, and multidisciplinary review of its ethical acceptability, 4. The persons undergoing research have been informed of their rights and the safeguards prescribed by law for their protection; 5. the necessary consent as provided for under Article 5 has been given expressly, specifically and is documented. Such consent may be freely withdrawn at any time.

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Article 17 – Protection of persons not able to consent to research 1. Research on a person without the capacity to consent as stipulated in Article 5 may be undertaken only if all the following conditions are met: i. the conditions laid down in Article 16, sub-paragraphs i to iv, are fulfilled; ii. the results of the research have the potential to produce real and direct benefit to his or her health; iii. research of comparable effectiveness cannot be carried out on individuals capable of giving consent; iv. the necessary authorisation provided for under Article 6 has been given specifically and in writing; and v. the person concerned does not object. 2 Exceptionally and under the protective conditions prescribed by law, where the research has not the potential to produce results of direct benefit to the health of the person concerned, such research may be authorised subject to the conditions laid down in paragraph 1, sub-paragraphs i, iii, iv and v above, and to the following additional conditions: i. the research has the aim of contributing, through significant improvement in the scientific understanding of the individual's condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to the person concerned or to other persons in the same age category or afflicted with the same disease or disorder or having the same condition; ii. the research entails only minimal risk and minimal burden for the individual concerned. Article 18 – Research on embryos in vitro 1. Where the law allows research on embryos in vitro, it shall ensure adequate protection of the embryo. 2. The creation of human embryos for research purposes is prohibited.

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CHAPTER VI – Organ and tissue removal from living donors for transplantation purposes Article 19 – General rule 1. Removal of organs or tissue from a living person for transplantation purposes may be carried out solely for the therapeutic benefit of the recipient and where there is no suitable organ or tissue available from a deceased person and no other alternative therapeutic method of comparable effectiveness. 2. The necessary consent as provided for under Article 5 must have been given expressly and specifically either in written form or before an official body. Article 20 – Protection of persons not able to consent to organ removal 1. No organ or tissue removal may be carried out on a person who does not have the capacity to consent under Article 5. 2. Exceptionally and under the protective conditions prescribed by law, the removal of regenerative tissue from a person who does not have the capacity to consent may be authorised provided the following conditions are met: i. there is no compatible donor available who has the capacity to consent; ii. the recipient is a brother or sister of the donor; iii. the donation must have the potential to be life-saving for the recipient; iv. the authorisation provided for under paragraphs 2 and 3 of Article 6 has been given specifically and in writing, in accordance with the law and with the approval of the competent body; v. the potential donor concerned does not object. CHAPTER VII – Prohibition of financial gain and disposal of a part of the human body Article 21 – Prohibition of financial gain The human body and its parts shall not, as such, give rise to financial gain.

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Article 22 – Disposal of a removed part of the human body When in the course of an intervention any part of a human body is removed, it may be stored and used for a purpose other than that for which it was removed, only if this is done in conformity with appropriate information and consent procedures. CHAPTER X – Public debate Article 28 – Public debate Parties to this Convention shall see to it that the fundamental questions raised by the developments of biology and medicine are the subject of appropriate public discussion in the light, in particular, of relevant medical, social, economic, ethical and legal implications, and that their possible application is made the subject of appropriate consultation. b. Explanatory report to the convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine: Convention on Human Rights and Biomedicine http://conventions.coe.int/Treaty/en/Reports/Html/164.htm 2.2. Convention on Biomedical Research Additional Protocol to the Convention on Human Rights and Biomedicine, on Biomedical Research. Strasbourg, 25.I.2005 http://conventions.coe.int/Treaty/EN/Treaties/Html/195.htm The following articles have an immediate impact on the development of TE: CHAPTER I – Object and scope Article 1 – Object and purpose Parties to this Protocol shall protect the dignity and identity of all human beings and guarantee everyone, without discrimination, respect for their integrity and other rights and fundamental freedoms with regard to any research involving interventions on human beings in the field of biomedicine.

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CHAPTER II – General provisions Article 3 – Primacy of the human being The interests and welfare of the human being participating in research shall prevail over the sole interest of society or science. Article 5 – Absence of alternatives Research on human beings may only be undertaken if there is no alternative of comparable effectiveness. Article 6 – Risks and benefits 1. Research shall not involve risks and burdens to the human being disproportionate to its potential benefits. 2. In addition, where the research does not have the potential to produce results of direct benefit to the health of the research participant, such research may only be undertaken if the research entails no more than acceptable risk and acceptable burden for the research participant. This shall be without prejudice to the provision contained in Article 15 paragraph 2, sub-paragraph ii for the protection of persons not able to consent to research. Article 7 – Approval Research may only be undertaken if the research project has been approved by the competent body after independent examination of its scientific merit, including assessment of the importance of the aim of research, and multidisciplinary review of its ethical acceptability.

Article 8 – Scientific quality Any research must be scientifically justified, meet generally accepted criteria of scientific quality and be carried out in accordance with relevant professional obligations and standards under the supervision of an appropriately qualified researcher. CHAPTER III – Ethics committee Article 9 – Independent examination by an ethics committee

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1. Every research project shall be submitted for independent examination of its ethical acceptability to an ethics committee. Such projects shall be submitted to independent examination in each State in which any research activity is to take place. 2. The purpose of the multidisciplinary examination of the ethical acceptability of the research project shall be to protect the dignity, rights, safety and well-being of research participants. The assessment of the ethical acceptability shall draw on an appropriate range of expertise and experience adequately reflecting professional and lay views. 3. The ethics committee shall produce an opinion containing reasons for its conclusion. Article 10 – Independence of the ethics committee 1. Parties to this Protocol shall take measures to assure the independence of the ethics committee. That body shall not be subject to undue external influences. 2. Members of the ethics committee shall declare all circumstances that might lead to a conflict of interest. Should such conflicts arise, those involved shall not participate in that review. Article 11 – Information for the ethics committee 1. All information which is necessary for the ethical assessment of the research project shall be given in written form to the ethics committee. 2. In particular, information on items contained in the appendix to this Protocol shall be provided, in so far as it is relevant for the research project. The appendix may be amended by the Committee set up by Article 32 of the Convention by a two-thirds majority of the votes cast. Article 12 – Undue influence The ethics committee must be satisfied that no undue influence, including that of a financial nature, will be exerted on persons to participate in research. In this respect, particular attention must be given to vulnerable or dependent persons.

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CHAPTER IV – Information and consent Article 13 – Information for research participants 1. The persons being asked to participate in a research project shall be given adequate information in a comprehensible form. This information shall be documented. 2. The information shall cover the purpose, the overall plan and the possible risks and benefits of the research project, and include the opinion of the ethics committee. Before being asked to consent to participate in a research project, the persons concerned shall be specifically informed, according to the nature and purpose of the research: i. of the nature, extent and duration of the procedures involved, in particular, details of any burden imposed by the research project; ii. of available preventive, diagnostic and therapeutic procedures; iii. of the arrangements for responding to adverse events or the concerns of research participants; iv. of arrangements to ensure respect for private life and ensure the confidentiality of personal data; v. of arrangements for access to information relevant to the participant arising from the research and to its overall results; vi. of the arrangements for fair compensation in the case of damage; vii. of any foreseen potential further uses, including commercial uses, of the research results, data or biological materials; viii. of the source of funding of the research project. 3. In addition, the persons being asked to participate in a research project shall be informed of the rights and safeguards prescribed by law for their protection, and specifically of their right to refuse consent or to withdraw consent at any time without being subject to any form of discrimination, in particular regarding the right to medical care. Article 14 – Consent 1. No research on a person may be carried out, subject to the provisions of both Chapter V and Article 19, without the informed, free, express, specific and documented consent of the person. Such

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consent may be freely withdrawn by the person at any phase of the research. 2. Refusal to give consent or the withdrawal of consent to participation in research shall not lead to any form of discrimination against the person concerned, in particular regarding the right to medical care. 3. Where the capacity of the person to give informed consent is in doubt, arrangements shall be in place to verify whether or not the person has such capacity. CHAPTER V – Protection of persons not able to consent to research Article 15 – Protection of persons not able to consent to research 1. Research on a person without the capacity to consent to research may be undertaken only if all the following specific conditions are met: i. the results of the research have the potential to produce real and direct benefit to his or her health; ii. research of comparable effectiveness cannot be carried out on individuals capable of giving consent; iii. the person undergoing research has been informed of his or her rights and the safeguards prescribed by law for his or her protection, unless this person is not in a state to receive the information; iv. the necessary authorisation has been given specifically and in writing by the legal representative or an authority, person or body provided for by law, and after having received the information required by Article 16, taking into account the person’s previously expressed wishes or objections. An adult not able to consent shall as far as possible take part in the authorisation procedure. The opinion of a minor shall be taken into consideration as an increasingly determining factor in proportion to age and degree of maturity; v. the person concerned does not object. 2. Exceptionally and under the protective conditions prescribed by law, where the research has not the potential to produce results of direct benefit to the health of the person concerned, such research

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may be authorised subject to the conditions laid down in paragraph 1, sub-paragraphs ii, iii, iv, and v above, and to the following additional conditions: i. the research has the aim of contributing, through significant improvement in the scientific understanding of the individual's condition, disease or disorder, to the ultimate attainment of results capable of conferring benefit to the person concerned or to other persons in the same age category or afflicted with the same disease or disorder or having the same condition; ii. the research entails only minimal risk and minimal burden for the individual concerned; and any consideration of additional potential benefits of the research shall not be used to justify an increased level of risk or burden. 3. Objection to participation, refusal to give authorisation or the withdrawal of authorisation to participate in research shall not lead to any form of discrimination against the person concerned, in particular regarding the right to medical care. Article 16 – Information prior to authorisation 1. Those being asked to authorise participation of a person in a research project shall be given adequate information in a comprehensible form. This information shall be documented. 2. The information shall cover the purpose, the overall plan and the possible risks and benefits of the research project, and include the opinion of the ethics committee. They shall further be informed of the rights and safeguards prescribed by law for the protection of those not able to consent to research and specifically of the right to refuse or to withdraw authorisation at any time, without the person concerned being subject to any form of discrimination, in particular regarding the right to medical care. They shall be specifically informed according to the nature and purpose of the research of the items of information listed in Article 13. 3. The information shall also be provided to the individual concerned, unless this person is not in a state to receive the information.

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CHAPTER VII – Safety and supervision Article 21 – Minimisation of risk and burden 1. All reasonable measures shall be taken to ensure safety and to minimise risk and burden for the research participants. 2. Research may only be carried out under the supervision of a clinical professional who possesses the necessary qualifications and experience. Article 22 – Assessment of health status 1. The researcher shall take all necessary steps to assess the state of health of human beings prior to their inclusion in research, to ensure that those at increased risk in relation to participation in a specific project be excluded. Article 23 – Non-interference with necessary clinical interventions 1. Research shall not delay nor deprive participants of medically necessary preventive, diagnostic or therapeutic procedures. 2. In research associated with prevention, diagnosis or treatment, participants assigned to control groups shall be assured of proven methods of prevention, diagnosis or treatment. 3. The use of placebo is permissible where there are no methods of proven effectiveness, or where withdrawal or withholding of such methods does not present an unacceptable risk or burden. Article 24 – New developments 1. Parties to this Protocol shall take measures to ensure that the research project is re-examined if this is justified in the light of scientific developments or events arising in the course of the research. 2. The purpose of the re-examination is to establish whether: i. the research needs to be discontinued or if changes to the research project are necessary for the research to continue; ii. research participants, or if applicable their representatives, need to be informed of the developments or events; iii. additional consent or authorisation for participation is required.

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3. Any new information relevant to their participation shall be conveyed to the research participants, or, if applicable, to their representatives, in a timely manner. 4. The competent body shall be informed of the reasons for any premature termination of a research project. CHAPTER VIII – Confidentiality and right to information Article 25 – Confidentiality 1. Any information of a personal nature collected during biomedical research shall be considered as confidential and treated according to the rules relating to the protection of private life. 2. The law shall protect against inappropriate disclosure of any other information related to a research project that has been submitted to an ethics committee in compliance with this Protocol. Article 26 – Right to information 1. Research participants shall be entitled to know any information collected on their health in conformity with the provisions of Article 10 of the Convention. 2. Other personal information collected for a research project will be accessible to them in conformity with the law on the protection of individuals with regard to processing of personal data. Article 27 – Duty of care If research gives rise to information of relevance to the current or future health or quality of life of research participants, this information must be offered to them. That shall be done within a framework of health care or counseling. In communication of such information, due care must be taken in order to protect confidentiality and to respect any wish of a participant not to receive such information. Article 28 – Availability of results 1. On completion of the research, a report or summary shall be submitted to the ethics committee or the competent body.

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2. The conclusions of the research shall be made available to participants in reasonable time, on request. 3. The researcher shall take appropriate measures to make public the results of research in reasonable time. CHAPTER IX – Research in States not parties to this Protocol Article 29 – Research in States not parties to this Protocol Sponsors or researchers within the jurisdiction of a Party to this Protocol that plan to undertake or direct a research project in a State not party to this Protocol shall ensure that, without prejudice to the provisions applicable in that State, the research project complies with the principles on which the provisions of this Protocol are based. Where necessary, the Party shall take appropriate measures to that end. Appendix: Information to be given to the ethics committee Information on the following items shall be provided to the ethics committee, in so far as it is relevant for the research project: Description of the project i. the name of the principal researcher, qualifications and experience of researchers and, where appropriate, the clinically responsible person, and funding arrangements; ii. the aim and justification for the research based on the latest state of scientific knowledge; iii. methods and procedures envisaged, including statistical and other analytical techniques; iv. a comprehensive summary of the research project in lay language; v. a statement of previous and concurrent submissions of the research project for assessment or approval and the outcome of those submissions; Participants, consent and information vi. justification for involving human beings in the research project;

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vii. the criteria for inclusion or exclusion of the categories of persons for participation in the research project and how those persons are to be selected and recruited; viii. reasons for the use or the absence of control groups; ix. a description of the nature and degree of foreseeable risks that may be incurred through participating in research; x. the nature, extent and duration of the interventions to be carried out on the research participants, and details of any burden imposed by the research project; xi. arrangements to monitor, evaluate and react to contingencies that may have consequences for the present or future health of research participants; xii. the timing and details of information for those persons who would participate in the research project and the means proposed for provision of this information; xiii. documentation intended to be used to seek consent or, in the case of persons not able to consent, authorisation for participation in the research project; xiv. arrangements to ensure respect for the private life of those persons who would participate in research and ensure the confidentiality of personal data; xv. arrangements foreseen for information which may be generated and be relevant to the present or future health of those persons who would participate in research and their family members; Other information xvi. details of all payments and rewards to be made in the context of the research project; xvii. details of all circumstances that might lead to conflicts of interest that may affect the independent judgment of the researchers; xviii. details of any foreseen potential further uses, including commercial uses, of the research results, data or biological materials; xix. details of all other ethical issues, as perceived by the researcher;

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xx. details of any insurance or indemnity to cover damage arising in the context of the research project. The ethics committee may request additional information necessary for evaluation of the research project. 2.3. Cell, tissue and organ transplants Additional Protocol to the Convention on Human Rights and Biomedicine, on Transplantation of Organs and Tissues of Human Origin. Strasbourg, 24.I.2002 http://conventions.coe.int/treaty/en/treaties/html/186.htm The following articles have an immediate impact on the development of TE: CHAPTER I- Object and Scope Article 2 – Scope and definitions 1. This Protocol applies to the transplantation of organs and tissues of human origin carried out for therapeutic purposes. 2. The provisions of this Protocol applicable to tissues shall apply also to cells, including haematopoietic stem cells. 3. The Protocol does not apply: a to reproductive organs and tissue; b to embryonic or foetal organs and tissues; c to blood and blood derivatives. 4 For the purposes of this Protocol: – the term "transplantation" covers the complete process of removal of an organ or tissue from one person and implantation of that organ or tissue into another person, including all procedures for preparation, preservation and storage; – subject to the provisions of Article 20, the term "removal" refers to removal for the purposes of implantation.

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CHAPTER II – General provisions Article 4 – Professional standards Any intervention in the field of organ or tissue transplantation must be carried out in accordance with relevant professional obligations and standards. Article 5 – Information for the recipient The recipient and, where appropriate, the person or body providing authorisation for the implantation shall beforehand be given appropriate information as to the purpose and nature of the implantation, its consequences and risks, as well as on the alternatives to the intervention. Article 6 – Health and safety All professionals involved in organ or tissue transplantation shall take all reasonable measures to minimise the risks of transmission of any disease to the recipient and to avoid any action which might affect the suitability of an organ or tissue for implantation. Article 7 – Medical follow-up Appropriate medical follow-up shall be offered to living donors and recipients after transplantation. Article 8 – Information for health professionals and the public Parties shall provide information for health professionals and for the public in general on the need for organs and tissues. They shall also provide information on the conditions relating to removal and implantation of organs and tissues, including matters relating to consent or authorisation, in particular with regard to removal from deceased persons. CHAPTER III – Organ and tissue removal from living persons Article 9 – General rule Removal of organs or tissue from a living person may be carried out solely for the therapeutic benefit of the recipient and where

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there is no suitable organ or tissue available from a deceased person and no other alternative therapeutic method of comparable effectiveness. Article 10 – Potential organ donors Organ removal from a living donor may be carried out for the benefit of a recipient with whom the donor has a close personal relationship as defined by law, or, in the absence of such relationship, only under the conditions defined by law and with the approval of an appropriate independent body. Article 11 – Evaluation of risks for the donor Before organ or tissue removal, appropriate medical investigations and interventions shall be carried out to evaluate and reduce physical and psychological risks to the health of the donor. The removal may not be carried out if there is a serious risk to the life or health of the donor. Article 12 – Information for the donor The donor and, where appropriate, the person or body providing authorisation according to Article 14, paragraph 2, of this Protocol, shall beforehand be given appropriate information as to the purpose and nature of the removal as well as on its consequences and risks. They shall also be informed of the rights and the safeguards prescribed by law for the protection of the donor. In particular, they shall be informed of the right to have access to independent advice about such risks by a health professional having appropriate experience and who is not involved in the organ or tissue removal or subsequent transplantation procedures. Article 13 – Consent of the living donor Subject to Articles 14 and 15 of this Protocol, an organ or tissue may be removed from a living donor only after the person concerned has given free, informed and specific consent to it either in written form or before an official body. The person concerned may freely withdraw consent at any time.

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Article 14 – Protection of persons not able to consent to organ or tissue removal 1 No organ or tissue removal may be carried out on a person who does not have the capacity to consent under Article 13 of this Protocol. 2 Exceptionally, and under the protective conditions prescribed by law, the removal of regenerative tissue from a person who does not have the capacity to consent may be authorised provided the following conditions are met: i there is no compatible donor available who has the capacity to consent; ii the recipient is a brother or sister of the donor; iii the donation has the potential to be life-saving for the recipient; iv the authorisation of his or her representative or an authority or a person or body provided for by law has been given specifically and in writing and with the approval of the competent body; v the potential donor concerned does not object. Article 15 – Cell removal from a living donor The law may provide that the provisions of Article 14, paragraph 2, indents ii and iii, shall not apply to cells insofar as it is established that their removal only implies minimal risk and minimal burden for the donor. CHAPTER V – Implantation of an organ or tissue removed for a purpose other than donation for implantation Article 20 – Implantation of an organ or tissue removed for a purpose other than donation for implantation 1 When an organ or tissue is removed from a person for a purpose other than donation for implantation, it may only be implanted if the consequences and possible risks have been explained to that person and his/her informed consent, or appropriate authorisation in the case of a person not able to consent, has been obtained .

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2 All the provisions of this Protocol apply to the situations referred to in paragraph 1, except for those in Chapter III and IV. CHAPTER VI – Prohibition of financial gain Article 21 – Prohibition of financial gain 1 The human body and its parts shall not, as such, give rise to financial gain or comparable advantage. The aforementioned provision shall not prevent payments which do not constitute a financial gain or a comparable advantage, in particular: – compensation of living donors for loss of earnings and any other justifiable expenses caused by the removal or by the related medical examinations; – payment of a justifiable fee for legitimate medical or related technical services rendered in connection with transplantation; – compensation in case of undue damage resulting from the removal of organs or tissues from living persons. 2 Advertising the need for, or availability of, organs or tissues, with a view to offering or seeking financial gain or comparable advantage, shall be prohibited. Article 22 – Prohibition of organ and tissue trafficking Organ and tissue trafficking shall be prohibited. CHAPTER VII – Confidentiality Article 23 – Confidentiality 1 All personal data relating to the person from whom organs or tissues have been removed and those relating to the recipient shall be considered to be confidential. Such data may only be collected, processed and communicated according to the rules relating to professional confidentiality and personal data protection. 2 The provisions of paragraph 1 shall be interpreted without prejudice to the provisions making possible, subject to appropriate safeguards, the collection, processing and communication of the necessary information about the person

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from whom organs or tissues have been removed or the recipient(s) of organs and tissues in so far as this is required for medical purposes, including traceability, as provided for in Article 3 of this Protocol. CHAPTER VIII – Infringements of the provisions of the Protocol Article 24 – Infringements of rights or principles Parties shall provide appropriate judicial protection to prevent or to put a stop to an unlawful infringement of the rights and principles set forth in this Protocol at short notice. Article 25 – Compensation for undue damage The person who has suffered undue damage resulting from transplantation procedures is entitled to fair compensation according to the conditions and procedures prescribed by law. Article 26 – Sanctions Parties shall provide for appropriate sanctions to be applied in the event of infringement of the provisions contained in this Protocol. 2.4. Various subjects Compendium of Texts of the Council of Europe on Bioethical Matters. Vol. I http://www.coe.int/t/e/legal_affairs/legal_cooperation/bioethics/Texts_ and_documents/INF_2005_2e%20vol%20I%20textes%20CoE%20bio ethique.pdf Subjects: Contains resolutions and recommendations of the Committee of Ministers, the Convention on Human Rights and Biomedicine and its additional Protocols Autologous cord blood banks (rec (2004)8), Clinical trials, products from blood, plasma (rec R (93)4), Data banks (rec R (81)1, Human tissue banks (rec R (94)1), International exchange and transportation of human substances (rec R (79)5), Medical research on human beings (rec R (90)3), Protection medical data (rec R (97)5), Removal,

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grafting, transplantation human substances (resolution (78)29), Xenotransplantation (rec (2003)10; Xenotransplantation (rec R (97)15) Compendium of texts of the Council of Europe on Bioethical Matters. Volume II. http://www.coe.int/t/e/legal_affairs/legal_cooperation/bioethics/Texts_ and_documents/INF_2005_2e%20vol%20II%20textes%20CoE%20bi oethique.pdf Subjects: Contains recommendations, resolutions and opinions of the Parliamentary Assembly; resolutions from ministerial conferences and principles set out in the report of the ad hoc committee of experts on progress in the biomedical sciences (CAHBI). Human stem cell research (Rec 1352), Intellectual property (Rec 1425), Patenting (Rec 1240), Xenotransplantation (Rec 1399) 3. European Group on Ethics 3.1. Report of the European Group on Ethics on the ethical aspects of human tissue engineered products http://europa.eu.int/comm/european_group_ethics/docs/humantissuepr od.pdf The following points were made with regard to the development of TE: a. Information and consent All relevant facts which would affect the donor’s decision to consent or refuse should ideally be presented. The “free nature” of the donation entails the right to refuse without this having any negative consequences for the person asked to donate. – Research and development in this area is dynamic and rapid. The Group notes that it may have been impossible, in particular regarding tissue already stored for a long time, to inform the donor of the potential future use of the donated tissue for producing engineered product. It would be logistically difficult to trace the donor to obtain a new consent. Furthermore, the tissue is sometimes anonymously stored. Special provision should be considered for these cases.

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– From now on, the possibility of potential future uses still unforeseeable should be made clear to the donor and different options of consent should be proposed. The point where withdrawing of consent will not be possible anymore should also be made explicit. – Donated tissue can be considered to be used for research purposes, but that covers a very broad category of potential uses which can be narrowed down in a number of ways. The EGE thinks that this is a problem to be considered more specifically. – The Directive 2004/23/EC regarding quality and safety of human tissues and cells addresses in article 13 the question of consent by referring to the national legal requirements regarding consent. The Group is of the opinion that this prevision should be reconsidered in the context of enlargement and in view of the integration of the Charter of Fundamental rights in the future European constitution. – The Group insists that the consent form should not be too broad or vague and that the consent is necessary whatever is the context of obtaining the tissue, for instance also in case of collection of surgical waste. Special considerations should be made regarding proxy consent and when consent is required there should be a clear option to refuse specific future uses. b. Donation There are different views on the individual’s freedom to decide about his/her tissue in relation with the common good. From some points of view the personal will has to be always prevalent while from other points of view the needs to solve particular health problems may have to be considered. – The question of donation is dealt with differently in different countries. If the consequences of donation are that the donor loses control of the use of the tissue, the possibility of different future uses should be part of the information to the donor. In some countries, the donor is allowed to control the future uses of the donated tissue even after donation. – The question of donation is linked to the question of ownership which is regarded differently in Anglo-Saxon and Latin cultures. According to the one approach, the donor after donation loses the control of the use of the tissue. In another approach, one has a

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personal right on one’s body, even after donation, so that one may accept or veto future uses of the donated tissue. c. Privacy/ data protection There may be conflicting interests between, on the one hand, the donor regarding respect of privacy, anonymity and the protection of the confidentiality of information collected during tissue procurement, and on the other hand, the recipient regarding the safety of the treatment implying traceability requirements. Strict data protection rules with the use of appropriate coding systems are necessary to reconcile both donor’s and recipient’s interests and prevent misuse of personal data or/and transmission of health data to third parties (in particular employers and insurance companies). d. Traceability The Group considers that the question of traceability of engineered tissues deserves a more in depth reflection. This includes what is meant by traceability, how far should it go and how to include it in the consent form. To be efficient, traceability must be complete. The more precise the traceability requirements are, the better the safety will be. e. Safety The Directive adopted on 2nd March 2004 on the “quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells” and the draft regulation prepared by DG Enterprise on human tissue engineered products, contribute to establish health rules at Community level as called upon by the EGE Opinion 11 (on tissue banking). Specific care has to be taken explicitly in the use of genetically modified organisms in TE as they can raise specific safety problems. Generally all safety requirements and evaluations of risk and efficiency should be explicitly detailed in the regulation. f. Priorities of access “The medical use of products of human origin is inevitably constrained by limited availability, owing to the precautions that

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have to be taken to guarantee safety and to the voluntary nature of donations. According to the principle of justice, it is necessary to define the criteria for priority access to such tissue products in the most transparent manner possible, on the basis of an objective evaluation of medical needs, taking into consideration the objectives for public health in Europe” (point 2.9 of Opinion 11) g. Research and clinical trials Free and informed consent Free and informed consent is required not only from the donor but also from the recipient as stated in the Group's opinion on Human Tissue Banking (21/07/1998). In each case, it is necessary to inform the donor (the woman or the couple) of the possible use of the embryonic cells for the specific purpose in question before requesting consent.

Risk-benefit assessment Risk-benefit assessment is crucial in stem cell research, as in any research, but is more difficult as the uncertainties are considerable given the gaps in our knowledge. Attempts to minimise the risks and increase the benefits should include optimising the strategies for safety. It is not enough to test the cultured stem cells or tissues derived from them for bacteria, viruses or toxicity. Safety and security aspects are of utmost importance in the transplantation of genetically modified cells and when stem cells are derived from somatic cells. For example, the risks that transplanted stem cells cause abnormalities or induce creation of tumours or cancers have to be assessed. It is important that the potential benefits for the patients should be taken into account but not exaggerated. The grounds of a precautionary approach need to be taken into account.

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Protection of the health of persons involved in clinical trials The possibility that irreversible and potentially harmful changes are introduced in clinical applications of stem cell research should be minimised. Techniques enhancing the possibilities of reversibility should be used whenever possible. If, for example, genetically modified cells were encapsulated when they are transplanted in order to stimulate neural cell growth, it should be possible for the procedure to be reversed if something goes wrong. Scientific evaluation of stem cell use for therapeutic purposes It is urgent to outline strategies and specific requirements for the best evaluation of ethically sound and safe use of stem cells as means of therapy (gene therapy, transplantation, etc.). Such an evaluation should be done in collaboration with the European Agency for the Evaluation of Medicinal Products. Anonymity of the donation Steps must be taken to protect and preserve the identity of both the donor and the recipient in stem cell research and use. As stated in the EGE's Opinion on Human Tissue Banking (21/07/1998): "in the interests of anonymity, it is prohibited to disclose information that could identify the donor, and the recipient. In general, the donor should not know the identity of the recipient, nor should the recipient know the identity of the donor" h. Specific questions related to human tissue engineered products - The distinction between medical and cosmetic uses In the case that human cells or tissues are used in cosmetic products, then the distinction between therapeutic uses and cosmetics uses may be sometimes difficult to state, namely when the definition of health is not only related to the existence or not of a pathology but also refers to quality of life. A risk analysis must take into account the difference of benefit between cosmetic and therapeutic uses.

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- Embryo The Group has not addressed in depth this issue regarding specifically engineered tissues, but some members of the Group have strong ethical reservations regarding the use of embryonic cells as raw material for producing engineered tissues. The Group considers that when embryonic cells or tissues are used to obtain engineered products, information should be given to the users/patients in order to allow free choice. That is in line with Opinion 16: “The principle of free and informed consent of the donor which is also reflected in article 3 of the Charter of Fundamental Rights and in the Recital 26 of the 1998 EU Patent Directive stating “Whereas if an invention is based on biological material of human origin or if it uses such material, where a patent application is filed, the person from whose body the material is taken must have had an opportunity of expressing free and informed consent thereto, in accordance with national law”. i. Patent The issue at stake is the profit obtained with an invention resulting of the use of donated tissues. The file to be completed in order to obtain a patent should always include a proof of the informed consent of the donor. 3.2. Human tissue banking a. Ethical aspects of human tissue banking (general) http://europa.eu.int/comm/secreatariat_general/ethics/en/index.htm Subjects: Respect for human beings, their dignity and autonomy, the common good, safety and protection. Protection of the donor and the recipient (incl. informed consent, privacy, confidentiality, safety, no discrimination, fair access). Commercialisation of tissues. Privacy and confidentiality of information collected during tissue procurement. Preventing possible discrimination: solidarity, availability of tissues. Equitable access.

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b. Ethical aspects of umbilical cord blood banking http://europa.eu.int/comm/secretariat_general/ethics/en/index.htm Subjects: Ethical background: fundamental ethical principles, ethical concerns regarding tissue banking, specific concerns raised by cord blood banking for autologous uses, information to consumers/citizens, protection of vulnerable groups, recruitment of donors, fairness of access to health care. Need for donors from different ethnic groups and HLA-types, legitimacy of commercial cord blood banks, bankruptcy, fair access to cord blood bank products. 3.3. Adoption of an Opinion on Ethical Aspects of Human Stem Cell Research and Use http://europa.eu.int/comm/secretariat_general/ethics/en/index.htm Subjects: Ethical issues in therapeutic cloning, legal aspects of the use of human stem cells Perspectives of different religions and denominations on stem cell research. Legal issues. Overview of recommendations in human stem cell research issued by National Ethics Committees: France, UK, USA. 3.4. Patenting a. Ethical aspects of patenting inventions involving elements of human origin http://europa.eu.int/comm/secreatariat_general/ethics/en/index.htm Subjects: Refusal to grant a patent on an invention in so far as it infringes the rights of the person and respect for human dignity should be legally founded. Knowledge related to the human body or its elements is relevant to scientific discovery and cannot be patented. The human body, as well as its elements does not constitute patentable inventions. The human body can not be commercialised. No remuneration can be given to the person from whom the samples are retrieved. Informed and free consent. Information of citizens. b. Opinion on ethical questions arising from the commission proposal for a council directive on legal protection for biotechnological inventions

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http://ec.europa.eu/european_group_ethics/docs/opinion3_en.pdf Subjects: Principle of patentability of living matter; non-patentability of inventions whose publication or exploitation would offend against public policy or morality; protection of human dignity (incl. ban on genetic engineering for non-therapeutic purposes), against commercial exploitation of the human body. c. Opinion on the ethical aspects of patenting inventions involving human stem cells http://ec.europa.eu/european_group_ethics/docs/avis16_en.pdf Subjects: Basic ethical dilemma, content of the patent, sources of stem cells, cloning, protection of the donor, patents and further research and development, registry, patents and access to health care, ethical evaluation of patent applications. 3.5. Other new technologies A number of new technologies, other than TE, have also been reviewed by the EGE. Cells in HTEPs can be genetically altered. It is equally not unthinkable that in the future HTEPs will be developed that contain either nanomaterials or ICT implants. In that case, both the advices with regard to HTEPs and to these new technologies need to be taken into consideration. a. The ethical implications of gene therapy http://ec.europa.eu/european_group_ethics/docs/opinion4_en.pdf Subjects: Encouragement of somatic gene therapy at different necessary levels involving also research on bioethics; ethical evaluation of somatic gene therapy protocols requires processes assuring quality, transparency and efficiency of this evaluation without introducing any unnecessary delays to the treatment of patients; national supervisory bodies; helpfulness of harmonization and partial standardization of all European evaluation processes. Use of genetically modified organisms in clinical trials. Restriction of somatic gene therapy to serious diseases for which there is no other effective available treatment. Equal access to gene therapy. Regulations at European level of the risks and results of gene therapy technology.

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Publication of the conclusions of evaluations. Germ line therapy is not at the present time ethically acceptable. Promotion of public information and education. b. Opinion on the ethical aspects of nanomedicine http://ec.europa.eu/european_group_ethics/activities/docs/opinion_21_ nano_en.pdf Subjects: Fundamental values and rights: human dignity, integrity, autonomy, privacy, equity, fairness, pluralism and solidarity, subsidiarity. Assessment of risks and safety; need for prospective technology assessment, including consideration of social effects. Legal issues: regulatory issues, data protection; product liability, intellectual property rights; nanomedicine tests on the market. Information and consent. Economics and funding; communication and public trust. Ethical, legal and social implications. Ethical deliberation on the concept of humanity, human rights, social and political conflicts in relation to nanotechnology. Clinical research. Medical and nonmedical uses. Sharing of information, databases. c. Ethical aspects of ICT implants in the human body http://ec.europa.eu/european_group_ethics/docs/avis20_en.pdf Subjects: Fundamental values and rights. ICT implants and human dignity, ICT implants for health purposes: individual and the network, freedom of research, participation in research on ICT implants. ICT implants, minors and legally incapacitated persons, access to ICT implants for health purposes; irreversible ICT implants. ICT implants for non-medical purposes. Development of the information society. Public debate and information. Democracy and power. Need for regulation. Impact research and ICT devices. C.

Conclusion

The ethical principles formulated in the different documents that we have discussed can be summarised as follows:

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- Respect for fundamental human rights of all persons involved in research and therapy, i.e. the cell donor, the trial participant and the patient. - The primacy of the human being: the interests and welfare of the human being participating in research shall prevail over the interest of society or science. The prohibition to conduct research on human beings if there is an alternative of comparable effectiveness. No person should be unduly influenced to participate in research, through financial or other inducements. - The prohibition to make the human body and its parts as such the source of financial gain. Free and altruistic donation of cells. - Respect for privacy, including the protection of personal data and the guarantee to anonymity of cell donors and recipients. - The right to the integrity of the person, more explicitly the necessity to obtain free and informed consent of the person for every intervention for the purpose of research or medicine. During the informed consent process appropriate information in a comprehensible form should be given to the participant with regard to the procedure, its consequences and risks, alternatives, potential benefits, arrangements for responding to adverse events, for followup and all other relevant information. The person who is asked to consent needs to be informed of his rights, including the right to refuse or withdraw from the process in as far a possible, and in the case of research (not donation) of his right to relevant information to his current or future health or quality of life, and of the results of the research. The entitlement to any information collected about his health- and the right not to know. In the case of cell donation, the EGE suggests that the donor should also be informed of possible uses of the cells (including secondary use), and of his right to accept or refuse specific uses. Consent should not be too narrow or too vague. - The protection of minors and of people not able to give consent. Interventions/research on these persons can only be carried out under very strict conditions. - The protection of the trial participant and of the patient through the reduction of risks and the increase of potential benefits, through adequate pre-clinical research, risk-benefit assessments, reversibility, traceability and follow-up strategies.

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- The right to benefit from medical treatment. - Oversight by independent ethics committees of research, protecting the dignity, rights, safety and well being of research participants.

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IV.

ETHICAL QUESTIONS FOR HTEPs and TE

§ 1. Introduction: four approaches to TE and HTEPs in Europe and the ethical issues they raise As we have already indicated in the introduction of this European Ethical-Legal Paper, a wide range of perspectives is possible to address the ethical issues linked to the development and the application of TE. There is not only a need for an ethical analysis and ethical guidance for TE research and therapy sensu stricto. Some issues are beyond the scope of research ethics, but have nevertheless to be considered if we want to arrive at a full ethical appraisal of TE and its possible impact. Fig. 2 gives an overview of these approaches.

Anthropological approach

Socioeconomic aspects

Specific HTEPS

Research ethics

Figure 2: approaches toward the ethics of TE

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The ability to create HTEPs and to incorporate them into the body may reinforce or go against fundamental anthropological views held by European societies. Given the use of human derived material in HTEPs within the context of trade and enterprises, there are also issues with regard to the possible commodification of human beings and their bodily material. HTEPs will be expensive; therefore the availability and the socioeconomic impact of HTEPs must also be examined from an ethical point of view. This impact concerns not only the immediate effects of the application of the HTEP on health care budgets, but also the longterm impact of the capacity to regenerate tissues and thus to influence the ageing process. This can lead to demographical changes and result in significant changes in health care needs. Lastly, the development of HTEPs based on specific cells (e.g. xenogeneic material or human embryonic stem cells), of specific HTEPs (e.g. heart valves) or for certain patient populations (e.g. pediatric applications) raises yet other ethical questions. In this chapter we will examine the main ethical issues that are raised from these different perspectives. It is however far too early in the development of TE to reach an encompassing ethical opinion of TE and HTEPs. A number of the issues we have mentioned are already raised in the context of other medical developments. It is clear that the development of nanotechnology, gene therapy and somatic cell therapy may elicit similar ethical questions. The ethical debate that is going on in those domains may inform and influence the ethical debate with regard to TE and vice versa.

§ 2. Anthropological issues Discussions in the European Parliament, in the media and in journals, and a number of high-profile court cases in the USA (Andrews and Nelkin, 1998), are witness to the apparent and urgent need for the clarification of fundamental anthropological reference frames that underlie our perception of personhood, the human body and its components, and of their value. Allogeneic TE involves the use of donated human cells. The use of biological material (e.g. cells) for biomedical applications is

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widespread and has become the subject of intense debate. For TE this debate encompasses the impact the use of HTEPs may have on our interpretation of (1) what it means to be an embodied human being, (2) of our interpretation of the life cycle. (3) It may also influence the modalities for the exchange of human material and for the use of cells in order to produce HTEPs. A.

Interpretation of the meaning of the human body

The ability to create viable human tissues in vitro ‘from scratch’ is for some people a source of concern. This concern can be reinforced if particular cells (e.g. animal cells or embryonic stem cells) are used for these tissues, or if the HTEP is thought to give the body enhanced features. These concerns are closely linked with the interpretation of the meaning, the function and the limits of the human body and of the ways and means that are allowed in order to influence or change the body (Andrews and Nelkin, 2001; Waldby, 2006). These views are grounded in religious and philosophical views of personhood and embodiment and are often accompanied by moral pro- and prescriptions with regard to the body. They strongly influence people in their acceptance or rejection of TE as a technique, and of (certain types of) HTEPs. Different and opposing views with regard to the body (holistic views, Cartesian views…) are present in European societies and influence the interpretation of the different understandings of the value of the human body and its parts and of the meaning of HTEPs. The recognition of the importance of these reference frames for policy and public attitudes toward new medical developments already has been pointed out in other bio-ethical debates such as the debates on organ donation and stem cell research (Youngner, 2004; Bovenberg, 2005). B.

Changes in the life cycle.

The perspective of the in vitro creation of human tissue and regeneration of degenerated tissues to full physiological capacity raises possibilities that were previously thought impossible. TE presents, at least in theory, the possibility of altering the life cycle through the replacement of ageing tissues and thus delaying the ageing

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process. The alteration of the different stages of the life cycle has not only implications for the directly involved, but also for society as a whole, where the impact of an ageing society is already being felt. If HTEPs become widely available, this may not only alter the interpretation of the life cycle, it will also have an influence on the constitution of the general population, and thus also have a socioeconomic effect. We will explore these effects in §3 (p. 52). C.

Exchange of human material

The Charter of Fundamental Rights and the Convention on Biomedicine both stress the free, altruistic donation of bodily material, which gives the principle serious moral weight. All relevant European Directives insist on this principle, which makes free donation the legal norm in the context of TE. This approach to the exchange of bodily material is grounded in the principle that trading the human body or parts of it go against the dignity and the privacy of the human person (Herring and Chau, 2007). However, cells and tissues play an increasingly important role in the growing and global ‘tissue economies’ (Waldby and Mitchell, 2006), in which a complicated web is constructed between a large number of persons, and in which not only altruistic donation but also the selling, use and alteration of bodily material form the threads between all involved. In this context the fundamental reference frame is not so much one of dignity and autonomy, but one of ownership of the body. These tissue economies have an impact on the transition of tissue donation as a gift relationship (Titmuss, 1997) between donor and recipient (the traditional European approach) to a commercial relationship between a varying number of participants, which is to some extent already present, especially in the USA (Andrews and Nelkin, 1998). This transition will also have an impact on the use of bodily material as a means of expressing our relationship with each other, with society and with the world. A profound ethical evaluation of the different ways of exchanging human bodily material is already being conducted by some scholars (Waldby, 2006). The results of this research may inform us whether the free and altruistic donation of cells as it is inscribed in European Directives, Conventions and

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Protocols remains the best solution to protect the dignity and autonomy of all persons involved in the context of TE. The transition from a gift relationship to a commercial relationship will also have a bearing on issues such as the commodification of the body and/or parts of the body, and on the issue of ownership of bodily material. Bodily materials are generally not considered to be commodities in the generic sense of the word. They do however have some characteristics in common with commodities, such as the possibility to be transferred from one person to another or the possibility to alter them through the application of skills (Dickenson, 2002). It is therefore necessary to investigate which characteristics of bodily material need to be taken into account when considering issues such as commercialisation and ownership of these materials. The results of this research may inform the proper way of exchanging and using cells for TE.

§ 3. Socio-economic approach The development of TE also has social and economic consequences. We review two elements: the access to HTEPs by individual persons and the impact that TE may have on the organisation of health care systems. A.

Access to HTEPs

Access to HTEPs can be assessed from two perspectives: a biological perspective and a socio-economic perspective 1. Biological perspective The creation of HTEPs has to be seen as a continuous process in which (donated) cells form the basis for the later HTEP. When the HTEP contains autologous cells, there is no concern about the compatibility of donor and recipient. This problem is however crucial in allogeneic HTEPs. The importance of histocompatibility differs to some extent, depending on the exact source of cells for the HTEP that is used and on the particular application of the HTEP. It is known that stem cells

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that are derived from human umbilical cord blood are immunologically more ‘naïve’ than stem cells derived from bone marrow or fully differentiated cells. Consequently, such naïve stem cells can be given to a larger number of patients than cells that are immunologically more determined. Other features of the donated cells (e.g. the sex of the donor and recipient) may also influence the results. This implies that the choice of the cell source for the construction of the HTEP (both with regard to the cell type as to the donor), and the way that this sourcing will be regulated and conducted, will have an impact on the number of people that will be able to receive a biologically compatible HTEP. Choosing HTEPs that are less histocompatible, or that are for other reasons less suited will increase the risks attached to the HTEP considerably, and will lay an extra burden on the recipient of the HTEP in the form of the need for lifelong medication to suppress rejection or other negative side effects. Determining how strong the match between the cells in the HTEP and the donor needs to be in case of allogeneic HTEPs will be necessary according to this guidance, and how the availability of cells will be secured accordingly. One of the possible ways to ensure that a large number of cell types is available for TE is through the establishment of ‘open’ cell banks. Yet it will always be in the best interest of the recipient that the HTEP he or she receives is as compatible with his own tissues as possible. This can only be achieved if the variety of cell donors is large, and if the cells that are donated are accessible to all who might benefit from them. Consequently, efforts should be made to establish mechanisms that allow for the efficient and safe procurement and distribution of cells from all groups in the population. It also implies that populations that have so far not been reached or that have been reluctant to participate in donation schemes should be made aware of the consequences of their absence in the donation process. If these efforts are not made, the access of certain groups in the population to TE and HTEPs cannot always be guaranteed, purely on biological grounds. Experiences with organ donation, umbilical cord blood banking and bone marrow registries indicate that there are large disparities between

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social, religious and ethnic groups with regard to their willingness to participate in donation schemes of bodily material. The reasons for these differences may be varying, but ultimately lead to an underrepresentation of these groups’ cells and therefore also to a shortage of histocompatible cells, tissue and organs for treatment of these groups. Differences in the willingness to donate need to be anticipated, if we do not want to reproduce these disparities for HTEPs (Ballen, 2002; Callender, 1991). 2. Socio-economic perspective It is clear that the organisation of cell repositories also has economic and social implications. Creating a cell repository that is accessible to a large number of people, with a large number of samples, requires a different approach, and will be funded differently from a repository that is aimed at the storage of privately donated samples for autologous use. The choice between treatment with autologous material and allogeneic material is not a purely technical matter. In the case of autologous material, healthy cells can be removed from the person and stored in anticipation of the eventual need for them in a later stage of life. In the case of treatment with allogeneic material one depends upon a ‘pool’ of allogeneic cells that are deposited in cell banks or other repositories. In the first case there is no need for a large pool, one is assured that histocompatible material is at hand and no free access to the repository is mandatory. In the second case the public has an interest in creating as large a bank as possible: the more cell samples in the bank, the higher the probability that a sample will fit histocompatibility and other criteria and that an appropriate HTEP can be derived from them. Free access to publicly funded banks containing altruistically donated material should be mandatory for those in need of specific cells, and the distribution of their cells should be governed by objective criteria. Ideally a very large amount of different cell types from different donors should be established, in order to provide the appropriate cells for as many recipients as possible. Increasing the size of a bank will substantially raise the costs for establishing and maintaining it.

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Determining the acceptable size and costs of these banks will codetermine which part of the population will be able to benefit from HTEPs. Economic considerations can therefore interfere with the right to access for treatment. The example of umbilical cord blood banks suggests that the choice from the donor’s perspective either to donate to a public cord blood bank or to a private repository is a complex one. One of the main issues that inform the decision of individuals to donate to a public/private cord blood bank is the value that is given to the cells that are deposited in the bank. If cells have potentially such a large regenerative potential, their value as ‘insurance’ against ageing processes increases dramatically (Waldby, 2006). This increase will be even more significant if the development of TE will lead to the successful implant of various tissues. This increase in cell value is an important side-effect of our new ability to store and alter human cells, and to create immortalized cell lines. This change in the potential value of cells may have repercussions on the way people perceive the exchange of cells. The gift relationship as the expression of an altruistic attitude toward the other that lies at the basis of all relevant European documents, takes on a new dimension in light of the development of regenerative medicine and the increasing worth of human cells in the tissue economies. From the perspective of the producers of the HTEPs, other issues are at stake. The creation of HTEPs from autologous material leads to perfectly compatible products, but will also be an expensive and time consuming activity. Using allogeneic material reduces costs: one can make ‘batches’ for several patients instead of making a product that is tailor-made to fit one person. More importantly, using allogeneic material allows for some form of standardisation and a scaling up of the whole process of TE. Using allogeneic material also makes it possible to create ‘off-the-shelf’ HTEPs, which again reduces costs and increases economic viability of producers of HTEPs. Guaranteeing access to HTEPs to those who are most in need of them requires that HTEPs can be constructed that are as compatible as possible. Social, financial and logistic limitations will have an influence on the degree of compatibility that can reasonably be

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expected, and on the variety of people that have access to this new technology. One of the challenges for the future development of TE is to determine how possible discrimination can be prevented, and how HTEPs can be created and produced in a safe way, for an affordable price for all who are in need of them. What must be discussed with all stakeholders are the relationships between donors, cell providers, HTEP producers, surgeons, reimbursement agencies and patients, and their specific rights and obligations in order to guarantee maximal access and safety for all involved. B.

Organization of health care systems

The development and application of HTEPs may influence European health care in two respects: the conditions for the application and reimbursement of HTEPs, and the allocation of HTEPs to individuals. 1. Conditions for application and reimbursement HTEPs will be very expensive. Whether or not the development of TE leads to successful therapeutic applications and economically healthy enterprises will not only depend on scientific advances, but also on the modalities for the application and reimbursement of HTEPs. One of the main questions to be answered, therefore, is how HTEPs perform for specific therapies in comparison with existing treatments. The comparison of benefits and disadvantages of both HTEPs and existing therapies will decide whether and under which conditions HTEPS will be refunded. In this comparison one does not only have to assess the short and long-term safety of the HTEP, but also the shortand long-term efficacy and the increase in quality of life for the patient. Unfortunately, all these elements are notoriously difficult to assess. Making realistic prognoses with regard to the benefits and disadvantages of various HTEPs and with regard to the number of potential patients requires an insight into the total expenditure that can be expected if HTEPs become a realistic possibility for the treatment of degenerative diseases. If the supremacy of HTEPs over other therapies can be established, the effect of HTEPs on health care

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budgets may be considerable. If reimbursement is not provided, the application of the expensive HTEP will be the privilege of the happy few, and may prove to be economically unattractive. 2. Allocation of HTEPs The focus of TE- the regeneration of degenerative tissues- suggests that two groups of people will benefit especially from TE: young people with premature tissue degeneration, and elderly persons. The young will find a long term solution which is potentially superior to any yet available therapy for their condition. This will give them a higher quality of life over a longer period of time. The elderly suffer more than average from degenerative diseases, and will consequently benefit accordingly from the application of HTEPs. For example: the number of patients with Type II Diabetes is increasing as a result of the ageing population and of changing nutritional patterns. These patients are prone to develop diabetic foot ulcers, which can be treated with tissue engineered skin. Equally, the need for TE arteries to conduct coronary bypass surgery may rise, as will the demand for other applications of TE. The application of (expensive) HTEPs for elderly persons may have an influence on their life span, improving their life quality, but also lay a burden on the already stressed health care budgets. The allocation of HTEPs to specific patients or patient groups in the light of an ever more rising public health spending may demand that criteria are established in order to guarantee a fair and equitable access to these therapies for those most in need of them (European Commission, impact assessment, see p.10) . HTEPs will clearly add another element to the already complicated debate with regard to the just distribution of appropriate medical care.

§ 4. HTEPs as examples of regenerative medicine The development of HTEPs invites the question whether TE is sufficiently different from other innovations in order to raise specific ethical challenges with regard to the research leading up to the final product. In chapter II we have argued that TE as an example of

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regenerative medicine has indeed discrete characteristics that justifies specific attention. The following elements deserve closer attention: (1) the interests of the donor of the cells, (2) the importance and place of animal and clinical trials, (3) the conduct of clinical trials and (4) post-trial events. A.

The interests of the donor of the cells

No allogeneic HTEP can be produced without a donor. Given the need for metabolically active cells, it is most likely that the donor will be a living person, although theoretically persons meeting the requirements for organ donation after death could also become cell donors. Informed consent of the donor or his representative needs to be obtained before the prelevation of these cells. Donating cells for their use in TE applications necessitates an informed consent procedure and the signing of an informed consent form. The informed consent procedure will have to address on the one hand the information that has to be provided by the donor. It will also have to elaborate and the amount of information that is given to the donor. A potential conflict of interest rises between the donor of the cells and the future recipient of the cells (EGE, see p.38). While the recipient has the right to maximal safety, and therefore to as much information linked to the donated cells as possible, the donor has a right to privacy and confidentiality. These conflicting interests need to be resolved through good informed consent procedures, and through the use of tracing and data protection systems to guarantee the anonymity of donor and recipient, while still allowing to trace the HTEP and its components both upstream to the donor and downstream to the recipient. When considering the interests of the donor, one has to take into account that the donated cells have two different types of value. They contain informational value (genetic information, information related to life style) and material value (the metabolical, replicative and regenerative value of the cells)

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1. Informational value of the cells The construction or application of the HTEP may reveal previously unknown information about the donor’s genetic make-up or about the likelihood that he or she will develop certain conditions in a later stage of life. Therefore there is an incomplete ‘disentanglement’ between the donor, his or her cells and the HTEP that is derived from them. If we add to this incomplete disentanglement the traceability of HTEPs and their components both upstream and downstream, it is clear that the donor continues to have interests throughout the entire process of TE and the application of the HTEPs. The informational value associated with the cells remains important even when donating becomes an ‘act of separation’ or an ‘act of renunciation’ with regard to the material value of the cells from the donor. Informed consent procedures at the moment of cell donation will have to address the persistent informational value of the HTEP (and its possible importance for the donor) into consideration. 2. Material value Informed consent procedures will also have to address the issues related to the material value of the cells, and the interests of the donor in them (financial and otherwise). Donated cells can in some cases produce huge material value, either through the exertion of intellectual property rights on cells or cell lines, or through the production of new HTEPs (Knoppers and Hirtle, 1997, Waldby, 2006). Unlike the informational value of the cells which remains linked to the donor, the material value of the cells can be separated entirely from the donor through the stipulations of the informed consent form. In this respect the informed consent form takes on certain characteristics of a contract in which transfer of property is negotiated between donor and cell recipient.

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B.

Importance and place of animal and clinical trials

1. Animal trials The general rule with regard to the ethical conduct of clinical trials is that sufficient evidence about the possible benefits of the product or therapy under consideration has to be collected before proceeding to the clinical trial phase. Animal trials are generally considered to be essential links in the research leading up to a clinical trial. Unfortunately, the use of animal models to prove true regenerative activity caused by the HTEP is hampered by the fact that these models cannot fully mimic the complexity of the human environment. Equally, there are as yet no agreed standards and models for animal trials (Tawqeer, 2004). The use of animal models also carries ethical concerns. The value of animal trials is dependent on the relevant knowledge that can be gained from these trials. The limited applicability of animals to gather information on the efficacy and safety of the HTEP invites us to research the possibility to replace, reduce and refine the use of animals in such trials, and to investigate other possibilities of preclinical research (Armstrong, 2003). 2. Clinical trials The criteria to move from the pre-clinical trial phase to the clinical trial and from a phase III trial to therapeutic use are fairly well established for most types of trials. We have argued in chapter II that the demarcation between the different phases of the development and application of a HTEP is more blurred as a result of the continuity that is inherent to TE. When a HTEP is constructed and implanted in the body, it generates a dynamic. This is a long term process that might continue well beyond the duration of the trial. Adverse events, or secondary outcomes of the introduction of the HTEP, be they positive or negative, will therefore not necessarily be detected during the trial itself. These events, especially adverse events, will have to be monitored carefully over a long period of time after the end point of the clinical trial. Given the large costs of every trial, it is clear that the demarcation of the end

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point of the trial does not only involve safety issues, but also carries monetary considerations. However, the safety of the trial participant should get priority over all other issues. Therefore the end-point of the trial and post-trial follow-up schemes need to be worked out carefully, in order to minimise the risks for the trial participant. Trials of themselves will not be sufficient to make comprehensive projections about the future safety, efficacy and quality of the therapy; neither will they enable researchers to fully appreciate the long term changes in quality of life. Results gained from clinical trials should provide useful information about the future evolution of the HTEP once implanted; otherwise there is no point in starting a trial. Extrapolations of the data gathered during trials will allow making prognoses, but these will be based on assumptions, always containing a degree of uncertainty with regard to the long term effects. The actual long term effects can only be judged during the follow-up process, at least for as long as the interaction between HTEP and recipient continues to develop. In the light of this approach of TE as a long term and continuous process, it might be useful to reconsider the place and weight of the trial as an integrated part in the entire chain of production, testing and application of HTEPs. It might be useful to think of HTEPs as ‘therapies under control’ or of ‘technology under investigation’, rather than as therapies that have successfully passed the phase III-stage of trials. The notion of ‘therapy under control’ also implies that some governance of post-trial events needs to be established. C.

Conduct of clinical trials

The complexity of the TE process generates new questions with regard to the conduct of the clinical trial itself. The main challenges are (1) the aims of the trial, (2) the calculation of the risk/benefits balance, (3) the safety of the participant, (4) the autonomy of the participant and (5) the generalisability of the trial results.

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1. The aims of the trial A trial has two interlocking goals: a therapeutic one and a scientific one. Both goals must be achieved in the trial: the potential benefit for the patient must be at least strongly anticipated following the results of the preclinical research, while the actual regeneration of the body must also be established. If we consider the therapeutic aim of a trial with a HTEP, methodologies analogous to those of other trials can be applied and results can be compared (NICE, 2005). If we turn to the scientific goal of the trial, other targets must be reached. Given the fact that regenerative medicine is a new paradigm, clinical trials with HTEPs will have to address three specific issues: they will have to confirm that regenerative action of the HTEP takes place in vivo, how it takes place, and that both the introduction of living material and the interaction with the receiver’s body is safe and efficacious. For these issues, no comparison is possible with standard treatments because the regeneration of tissue is defined as being new and unique to the paradigm of regenerative medicine. Therefore, trials with HTEPs need to establish a tailored methodology that allows to determine the achievement of the set aims and to transfer the knowledge gained to other domains of regenerative medicine. In order to achieve these aims one has first to work out which parameters are indicative of true regenerative activity, and not merely of repair. 2. The calculation of the risks/benefits balance We have already indicated that the risks of TE can be serious. On the other hand, there are large benefits. It is clear that the risks/benefits balance is essential for an ethical evaluation of TE and HTEPs: no patient should enter a clinical trial if he/she is not aware of the possible consequences of this new therapy. The lack of knowledge with regard to induced regenerative processes and the varying amounts of risks related to specific HTEPs complicate the assessment of risks and benefits. The presence of other therapies which do perform adequately if not ideally, and are comparatively cheap, makes the calculation of the

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risk/benefit balance even more complex. To what degree must a HTEP promise to be superior to existing therapies in order to justify the application of a therapy that is inherently risky and of which we do not know the long term effects? And what is the acceptable degree of failed implants, requiring the removal of the HTEP or leading to even worse scenarios against the number of success stories leading to perfect regeneration? The presentation of risks and benefits of HTEPs and of possible alternatives must be at the core of the informed consent procedure. 3. The safety of the participant We have pointed out that not every product in the domain of regenerative medicine will carry the same risks. It is clear that our limited knowledge of the dynamics created by the introduction of HTEPS brings about specific safety challenges for the conduct of trials. A number of potential risks can be identified. (1) The quality and type of the cells and of the scaffolds. (2) The production and storage of the HTEP. The potential alteration of the genetic make-up during cell culture and expansion, the presence of unwanted cell types in the administered HTEP, and the maturity of the HTEP at the time of implantation need to be taken into consideration. Unfortunately, standard treatments to enhance the safety of a product are not necessarily appropriate or even applicable because HTEPs are dynamic, living structures. The yet to be fully developed Good Tissue Practices and Good Manufacturing Practices will consequently be crucial for the successful development of HTEPs. The skill of the surgeon implanting the finished HTEP will also have an impact on the final result and on the safety of the HTEP (Lilford, 2004). (3) It is of paramount importance that the dynamic between the HTEP and body which is generated can be monitored and controlled to detect and prevent undesired cell migration, propagation or (de)differentiation, to evoke rejection or inflammatory responses by the host’s body. The inherent variability of HTEPs makes the development of monitoring techniques and of procedures to reverse undesired evolutions even more important. A HTEP should not only prove its safety, it should also prove its efficacy. It clearly is not enough to provide evidence that a HTEP is

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not harmful. If the HTEP does not address the degeneration of the tissue, while another therapy does, than it would be irresponsible to conduct a trial or apply the product in therapy. If these safety and efficacy issues are not addressed satisfactorily, and given the fact that there are efficacious and safe alternatives, then it will be most questionable whether such a trial is ethically acceptable and whether any consent obtained from the patient will ever be adequate enough to figure as informed consent. 4. The autonomy of the participant The autonomy of the participant in the clinical trial needs to be respected. The main tool to guarantee this autonomy is the informed consent process that is reflected in the informed consent form as the end-point of this process. Given all the new elements that are involved in the development of HTEPs it is clear that obtaining a true informed consent will involve a large amount of information to the potential trial participant. As the first trials will not be able to benefit from earlier results in regenerative medicine, it will be difficult to give accurate information with regard to long term effects, side effects etc. It will also be difficult to give an accurate presentation of risks and benefits, except for general indications 5. The generalisability of the trial A clinical trial is set up to produce generalisable knowledge. We have assumed that the creation of a dynamic in the body is one of the main characteristics of TE, and that this dynamic entails a certain amount of variability in every application. Is it then possible to draw conclusions from the trial data that are generalisable enough to have any relevance for clinical practice or for a better understanding of the mechanisms of regenerative medicine? The well controlled settings of a clinical trial environment do not always mirror the factual conditions in which the tested therapy will be later applied. The articulation of the inclusion and exclusion criteria for the enrollment of participants in the trial is therefore of great importance, in order to be able to predict future positive

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outcomes, or to learn why specific HTEPs do work with certain patients, and not with others (Rothwell, 2005). One of the main tasks of clinical trials with HTEPs will therefore be to identify the key factors in the entire process of production and application of the HTEP that enable us to predict a beneficial outcome of the treatment and to reduce the degree of uncertainty to a minimum beyond the trial conditions. This task can only be realised satisfactorily if the HTEPs that are used in trials are fully documented and traceable, and if trials with HTEPs are combined with an extensive program that allows for long-term follow-up of a large number of patients with HTEPs. D.

Post-trial events

In order to evaluate the long-term performance of HTEPs, and to monitor for adverse events after the end-point of the trial, the establishment of a registry could be one of the crucial steps to take. Various registries have already been established for stem cells and medical devices. They could provide valuable insights concerning the data needed. An advantage of such a registry is the possibility to monitor larger numbers of people for adverse events or beneficial evolutions that might not become apparent in a single trial and/or during the post-trial period. Given the relatively small numbers of trial participants, certain correlations might only become visible through a meta-analysis of all data available (Krishnan, 2006; Rothwell, 2005). Another possible advantage of the registry is that the effects of the HTEP on certain population groups might be more easily identified and understood and that inclusion/exclusion criteria for prospective patients might be better definable, as well as relevant criteria for cell sourcing, scaffold construction and bioreactor functioning. To give but one example: the gender of the cells of the HTEP (derived from male or female donors) might have an effect on the efficacy of a HTEP related to the functioning of the cardiovascular system in males or females (Regitz-Zagoresk, 2006). Other favorable arguments for the setting up of such a registry are the possibility to provide a better follow-up service for patients who have received a HTEP, based on the experiences gained with other HTEPs,

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and the setting-up of an early-warning system for problems related to HTEPs. The quality of such a registry will largely depend on the amount and kind of data that are put in it. This not only means that as many participants as possible should be entered, with due respect for their consent and privacy, but also that as many relevant data as possible from the cell donor, from the HTEP production and from every patient should be included, such as gender, age and data influencing the incorporation of the HTEP. The establishment of such a registry will evoke important ethical and legal questions. Cell donors and patients must retain their right to privacy. The question is whether participation of the producers of HTEPs, including tissue banks, commercial enterprises, and academia in such a registry can be made obligatory and whether it is not contrary to other justifiable interests. While these questions need to be addressed, it seems to us that the value of such a registry can benefit the development of TE. It is encouraging that within the TE community the creation of such a registry is being considered (Williams, 2006c).

§ 5. Specific HTEPs and applications A.

Niche of HTEPs

One of the fundamental questions that needs to be solved with is the identification of the ‘niche’ of HTEPs. Enormous costs are associated with the development and production of a HTEP. However, the HTEPs that have been developed so far do not display such a qualitative superiority over existing treatments that their application is the obvious choice. New HTEPs will have to compete with other products and therapies, some already established, others still under investigation. Defining when a HTEP is so superior to other solutions that it merits the higher costs for development and production will be a challenge in itself. Ethical, socio-economic and anthropological issues will influence this assessment. It will be rendered even more difficult if the HTEP consists of ethically contentious cells, when the product is

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aimed at therapies that carry large risks, or when it is applied for specific population groups such as children. All these elements make it rather difficult to define the ‘niche’ of the HTEP. B.

Composition of the HTEP: specific cells and materials

The possibility to use particular cells as the starting point for the HTEP is a hotly debated issue. Generally speaking there are three main sources, each source having advantages and disadvantages. One can use (1) autologous cells, (2) allogeneic cells or (3) xenogeneic cells. Which source is the best does not only depend on its scientific and technical merits, but also- and in some cases in the first place- on the ethical ‘weight’ of these cells. 1. Autologous cells The use of autologous material, i.e. material from the patient him- or herself, does not produce many ethical issues of itself, as long as the biopsy performed to retrieve the necessary cells is done according to good clinical practice. Performing a biopsy presents a small extra safety risk for the patient that is not present if one uses allogeneic material, but apart from this slightly elevated risk, which can be easily controlled, there are no specific questions. 2. Allogeneic cells These cells, derived from a donor, pose both technical and ethical challenges. They can be fully differentiated or undifferentiated stem cells. In the latter case they can be adult stem cells or embryonic stem cells. Adult stem cells can be derived from several sources. Fully differentiated cells These cells are presently the source for HTEPs that are available for therapeutic purposes, but they show serious limitations with regard to their ability to proliferate in culture and with regard to their application. The main ethical issues are related to the conditions for obtaining these cells and tissues, i.e. the informed consent procedure

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and the modalities for the exchange of cells. These issues were discussed earlier in this European Ethical-Legal Paper. Adult stem cells Adult stem cells display a larger amount of plasticity than do fully differentiated cells, but not as much as human embryonic stem cells. Their differentiation can be induced in vitro, thus generating a wider variety of cell types. Deriving adult stem cells from donors encounters the same ethical problems as the isolation of fully differentiated cells. Embryonic stem cells The use of embryonic stem cells for TE and HTEPs is ethically the most sensitive issue. A debate concerning the acceptability of the use of human embryonic stem cells involving the destruction of human embryos has been going on since these cells were first isolated and their therapeutic potential was demonstrated. According to the principle of subsidiarity, it is up to the member states of the European Union to forbid, allow and regulate the isolation and use of human embryonic stem cells in research and therapy. Although current applications of TE are not yet using human embryonic stem cells, it is likely that HTEPs containing these cells will be developed. To restate T. Dobzhansky: nothing in embryonic stem cell research makes sense except in the light of regenerative medicine (Dobzhansky, 1973). The (non) acceptability of the isolation and use of embryonic stem cells in research and therapy is closely linked with anthropological considerations, grounded in fundamental philosophical and religious convictions. It is therefore unlikely that the widely differing views on this issue we find in Europe will easily be reconciled. This is not the kind of problem that can readily be ‘solved’. In practice the differences in opinion with regard to the acceptability of embryonic stem cells can lead to one of two approaches in TE: producers of HTEPs will restrict themselves to the development of HTEPs based on non-embryonic cells, or the pressure on countries

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that do not allow embryonic stem cells to accept these cells and the tissues derived from them will increase (Trommelmans, 2007). The proposal for a regulation on advanced therapy medicinal products refers to the principle of subsidiarity with regard to the use of human embryonic stem cells: ‘the regulation should not interfere with decisions made by Member States on whether to allow the use of any specific type of human cells, such as embryonic stem cells, or animal cells. It should also not affect the application of national legislation prohibiting or restricting the sale, supply or use of medicinal products containing, consisting of or derived from these cells’ (recital 6) 3. Xenogeneic material Another possible source for HTEPs are cells derived from non-human animals. HTEPs based on xenogeneic material are at this point in time not yet being developed, but extracorporeal devices containing nonhuman hepatocytes are being developed. Non-human cells pose important safety issues. Firstly, there is the immunological risk. Xenogeneic cells will have to be genetically altered or be physically isolated from the immune system of the recipient in order not to provoke a severe immunological response. Secondly, the possible transfer of viruses, especially if the donor animal is a pig, from animal to human poses serious health risks, not only for the recipient of the HTEP, but also for those who produce the HTEP and those who come into close contact with the recipient. The assessment of the risk/benefit ratio for applying these HTEPs therefore does not only concern the recipient of the HTEP- who has a presumed benefit, it also concerns third parties. These people clearly do not have the prospect of huge benefits, but do run serious risks which have to be taken into account when assessing the risk/benefit ratio. These risks will also influence the informed consent process- not only the recipient will have to agree to the procedure, other persons also have a stake and should be consulted. How far the demand for informed consent of persons not immediately involved in the application of this particular kind of HTEP can or must go, is an issue that needs thorough ethical reflection. How proscriptive the refusal of

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a ‘third party’ for the use of xenogeneic material can be needs to be investigated (Barker, H. and Polcack, L., 2001). A second major ethical issue which is linked to the use of xenogeneic cells is the fact that certain species of animals, in particular pigs and cows are regarded as unclean in certain religions (Daar, 1994; Enoch et al., 2005). Other persons reject the use of animals for human purposes on moral grounds. Potential recipients of HTEPs which contain these cells should at least be informed of the presence of these cells during the informed consent procedure. For the same reason it is advisable that the origin of extracellular material used as scaffold material in the HTEP should also be known and explained to the prospective recipient. Clear communication with regard to this subject, with individuals, but also with representatives of religious communities shows respect for the fundamental convictions of citizens and respects their autonomy and can generate an atmosphere of trust. C.

Applications for life threatening conditions

The range of possible applications of HTEPs is broad, including the regeneration of tissues for life threatening conditions such as TE heart valves and arteries for coronary bypass surgery. If these HTEPs are to be developed, the demand for adequate safety and reversibility measures is clear. One needs to ask how potentially fatal adverse events will be tackled. The reversibility of the procedure needs to be examined, but also the obligation of establishing back-up procedures. Will it for example be mandatory that in a trial with a tissue engineered heart valve or a tissue engineered organ a donor organ should be ready for the patient in case something goes wrong, at least in the early stages of experimentation or application? D.

Specific applications: pediatric applications

One of the potentially most beneficial applications of HTEPs is their use for pediatric applications. For example: the creation of TE heart valves that integrate and grow at the same rate as the child could be an

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enormous improvement compared to existing animal derived or synthetic heart valves. However, the application of new technology in minors is extensively regulated and demands that no qualitative comparable alternatives are available. It also requires even more guarantees with regard to the safety and efficacy of the treatment (European Commission, 2006).

§ 6. Final note: hype and hope We have already pointed out that the actual development of TE and HTEPs falls short of the expectations of many researchers. The number of HTEPs that is available for therapy is very small, and the number of new applications expected to become available soon is not encouraging. The main reason for this large gap between expectation and reality lies in the enormous complexity of the entire TE process, and in the connected safety issues. The creation of biomimetic material is fraught with practical problems, especially if one wants to create complex tissues and organs. Given this relatively slow development, it is unwise to create hype with regard to TE and HTEPs. The potential benefits of regenerative medicine are unmistakably huge, and the demand for HTEPs could increase enormously because of the ageing European population. Expectations with regard to the possibilities and benefits are consequently easily raised. These are however no valid arguments to create hype as long as the whole process of generating tissues from scratch is not fully understood, and cannot be conducted in a safe way throughout the entire process. It is the responsibility of the scientific community to communicate with the rest of society in a responsible manner and to present the state of their art in a realistic way, including the anticipated time frame needed to produce these products. It is also their duty, together with various regulatory bodies, to ensure that these products are produced in a safe and ethically sound way. Many people wait desperately for a solution for their painful condition. The huge possibilities of regenerative medicine tempt some scientists and investors to put claims in the media long before those

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claims can be supported by rigorous scientific research and facts, thus creating false hope for those in need of treatment. The creation of such hype can lead in the worst case scenario to unsafe and ethically unacceptable experiments or ‘therapies’ by charlatans, as has already been the case with ‘stem-cell therapies’ (Enserink, 2006). These ‘therapies’ will be applied to vulnerable and desperate people who lack the scientific background that enables them to evaluate the relevant literature, but who may be prepared to risk their lives based on the hype that is created by some scientists, investors and the media and exploited by these charlatans. It is the duty of scientists, media and regulators to present TE, both the technique and the ethical issues, in a realistic and responsible way.

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V. CONCLUDING REMARKS Tissue engineering is in its infancy. The importance of many of the issues we have addressed in this European Ethical-Legal Paper can therefore not yet be fully envisioned, but our analysis of tissue engineering as a complex and continuous process prompts us to argue that TE requires specific ethical attention at an early stage of its development. The development of tissue engineering from bench to bed should be accompanied by the awareness that anthropological views influence the interpretation of TE as a medical innovation and/or of certain HTEPs. In some instances this influence may be more important than the solution of technical issues. The analysis and presentation of these anthropological issues will also have an influence on the regulation of the tissue engineering process, e.g. on how the exchange of cells for tissue engineering will be governed. The generation of living human tissues in vitro, their integration in the body and the subsequent regeneration of the body invite a new reflection on the relationships between personhood and human body, and between the value that is attached to the entire body and to parts of the body. The future success of TE does not only depend upon its potential superiority as a medical intervention in comparison with other interventions, but also on its economic viability and its acceptance by the general public- which is not only the potential beneficiary of TE but also sponsors the research in and application of TE, and consists of potential cell donors. It is necessary to inform the general public about the state of the art in a realistic way, in understandable language and including the anticipated time frame to reach available therapy. Communication with the general public is the essential and first condition to generate trust in TE. Equally, the choice of HTEPs that will be developed may influence public acceptance. The determination of the ‘niche’ for HTEPs is not only a question of weighing economic risks and benefits, but also of 74

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producing those products that really make a medical difference, even when these products are needed by very few people. If the general public comes to perceive TE as a form of luxury surgery, only available to a limited number of people, or if they are produced with economic interests prevailing over medical interests, then public support could dwindle and turn into a rejection of the whole domain of TE. The economic viability of tissue engineering will not only be determined by the conditions for reimbursement of HTEPs. The stipulation of precise eligibility criteria for potential patients will influence the marketability of the HTEPs. Developments in other fields of medicine which may lead to alternative or better treatments will also influence this viability. The possibility to standardise and scale-up the production of HTEPs, the amount of required safety precautions, the type of cells used for the HTEP, the degree of required compatibility between donor and recipient and other issues will influence the costs for producing the HTEPs to a large extent and may make the production of these new products financially prohibitive. The willingness to accept HTEPs by surgeons and other health-care workers may also become an influential factor determining their economic viability. We have argued that the main ethical issues associated with the development of TE follow from the complexity and continuity that is unique and typical for the TE process. The dynamic interaction which is generated between the tissue engineered construct and the human body creates risks and safety issues that have not been encountered to that degree in other medical applications, and that have to be guided and monitored with great care. In order to conduct trials and therapy in an ethically responsible way, the assessment of benefits and risks, the reduction of risks and the improvement of the safety of the product must be of paramount concern. Also, the efficacy of the product and the therapy must prove to be superior to existing or new therapies. Unfortunately these challenges are very difficult to address, given the many unknowns that the new paradigm of regenerative medicine implies at the moment.

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The methodology of the trial, the clinical trial itself and the post-trial follow-up, they all need to be considered with the specific characteristics of the tissue engineering process in mind. Clinical trials will play a pivotal role in determining the safety and efficacy of HTEPs, but they have to be considered in close relationship with data found during the process of producing the HTEP and during post-trial follow-up and eventually also in relationship with the findings of therapy. Collecting and analysing data in a comprehensive registry may lead to safer and more efficacious HTEPs. Another field that deserves ethical scrutiny is the donation of cells for tissue engineering. These cells carry considerable value, both informational value and material value. Due to the continuity of the process, all participants in TE, from cell donor and tissue engineer to the recipient of the HTEP have, sometimes conflicting, interests with regard to the value of these cells. A number of important social, philosophical and anthropological values such as the respect for the dignity of human beings and the prohibition to turn the body or parts of it into a commodity lay at the basis of current European legislation with regard to the exchange of cells, and have governed these conflicts of interest until now. Given the quickly growing technical possibilities and socio-economic developments with regard to the use, value and exchange of human cells, the question rises whether current legislation is still the best approach to govern these potential conflicts and to protect the fundamental ethical principles. A thorough ethical analysis concerning the ownership and exchange of cells in the context of TE is needed, as is the development of guidance for the informed consent process and for the contents of the informed consent form in the specific context of tissue engineering. Currently the informed consent form not only recognises the duty to inform the donor about the procedure, its risks and potential benefits in donating cells. It also takes the form of a contract in which the donor signs away some or all of his/her rights to the cells he/she is donating and their value. As the potential value (material and informational) of the donated cells increases due to new scientific

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insights, technical advances and economic changes, the demand for clear informed consent documents and a clear informed consent process will also increase. The regulatory framework that is being developed for HTEPs rightly acknowledges the complexity and technicality of TE. This complexity and technicality will also influence the application of the general ethical principles stated in European Conventions, in the Charter of Fundamental Rights and other documents to TE research and therapy. The bottom line for all ethical guidance in TE must however remain the commitment of regulatory agencies and of HTEP producers and researchers to fundamental values: equitable access of patients to safe and efficacious products; respect for the autonomy and the rights of cell donors and patients and finally respect for the dignity of all involved in tissue engineering.

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VI. BIBLIOGRAPHY AHSAN, T. and NEREM, R., “Bioengineered tissues: the science, the technology, and the industry”, Orthod Craniofacial Res., 2005, 134140. ANDREWS, L. and NELKIN, D., “Whose body is it anyway? Disputes over body tissue in a biotechnology age”, The Lancet, 1998, 53- 61. ANDREWS, L. and NELKIN, D., “Body Bazaar. The market for human tissue in the biotechnology age”, Crown Publishers, New York, 2001, vii + 237p. ARMSTRONG, S.J. and BOTZLER, R.G. (ed.), “The animal ethics reader”, Routledge, London-New York, 2003. BALLEN, K.K. et al., “Racial and ethnic composition of volunteer cord blood donors: comparison with volunteer unrelated marrow donors in transfusion”, Transfusion, 2002, 1279-1284. BARKER, J.H. and POLCRACK, L., “Respect for persons, informed consent and the assessment of infectious disease risks in xenotransplantation”, Med. Health Care Philos., 2001, 53-70. BOVENBERG, J., “Whose Tissue is it Anyway?”, Nature Biotechnology, 2005, 929-933. CALLENDER, C.O., “Organ/tissue donation in African Americans: a national stratagem in the Surgeon General’s workshop on increasing organ donation: Background Papers, Washington DC, July 8-10, 1991”, 145-162, Washington DC: US Department of Health and Human Services, Public Health Service, 1991. DAAR, A.S., “Xenotransplantation and Religion: the Major Monotheist Religions”, Xeno, 1994, 61.

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DICKENSON, D., “Commodification of human tissue; implications for feminist and development ethics”, Developing World Bioethics, 2002, 55-63. DOBZHANSKY, T., “Nothing in biology makes sense except in the light of evolution”, American biology teacher, 1973, 125-129. EMANUEL, E. et al., “What makes clinical research ethical?”, JAMA, 2000, 2701-2711. ENOCH, S., SHAABAN, H. & DUNN, K.W., “Informed Consent Should Be Obtained from Patients to Use Products (Skin Substitutes) and Dressings Containing Biological Material”, J Med Ethics, 2005, 2-6. ENSERINK, M., “Selling the stem cell dream”, Science, 2006, 160163. EUROPEAN COMMISSION, “Ethical considerations for clinical trials performed in children. Recommendations of the a hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use”, 2006, http://ec.europa.eu/enterprise/pharmaceuticals/paediatrics/docs/paeds_ ethics_consultation20060929.pdf EUROPEAN COMMISSION, DG ENTERPRISE AND INDUSTRY. “Tissue engineering and beyond: summary of the 2005 public consultation on the draft proposal for a regulation on advanced therapies”, Brussels, 2005, http://ec.europa.eu/enterprise/pharmaceuticals/advtherapies/docs/2005 consultation-outcome-2005-11-18.pdf EUROPEAN COMMISSION. HEALTH AND CONSUMER PROTECTION DIRECTORATE-GENERAL. Opinion on the state of the art concerning tissue engineering. Adopted by the scientific committee on medicinal products and medical devices on 1st October 2001. Doc.SANCO/SCMPMD/2001/0006Final.

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http://ec.europa.eu/food/fs/sc/scmp/out37_en.pdf (accessed 12 Dec 06). FODOR, W., “Tissue engineering and cell based therapies, from the bench to the clinic: the potential to replace, repair and regenerate”, Reproductive biology and endocrinology, 2003, 102. HERRING, J. and CHAU, P.-L., “My Body, Your Body, Our Bodies”, Medical Law Review, 2007, 34-61. KNOPPERS, B.M. and HIRTLE, M., “Banking of Human Materials, Intellectual Property Rights and Ownership Issues: Emerging Trends in the Literature and International Policy Positions (part I)”, Law and the Human Genome Review 6, 1997. KRISHNAN S. et al. “Who is the ideal candidate for autologous chondrocyte implantation?”, J.Bone Joint Surg.[Br]., 2006, 61-64. LAVIK, E. and LANGER, R., “Tissue Engineering: Current State and Perspectives”, Appl Microbiol Biotechnol, 2004, 1-8. LILFORD, R. et al., “Trials in Surgery”, British Journal of Surgery, 2004, 6-16. NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE (NICE). “The use of autologous chondrocyte implantation for the treatment of cartilage defects in knee joints. Review of Technology Appraisal 16”, 2005, http://www.nice.org.uk/download.aspx?o=TA089guidance REGITZ-ZAGROSEK, V., “Therapeutic implications of the genderspecific aspects of cardiovascular disease”, Nature reviews Drug Discovery, 2006, ROTHWELL, P., “External Validity of randomised controlled trials: "To whom do the results of this trial apply?", Lancet, 2005, 82-93. TAWQEER, R. et al., “The use of animal models in developing the discipline of cardiovascular tissue engineering: a review.”, Biomaterials, 2004, 1627-1637.

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TROMMELMANS, L. et al., “A critical assessment of the Directive on tissue engineering of the European union”, Tissue Engineering, 2007, 667-672. TITMUSS, R., “The Gift relationship: From Human Blood to Social Policy”, ed. A. Oakley and J. Ashton. London: LSE, 1997 [1971]. U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES, FOOD AND DRUG ADMINISTRATION, CENTRE FOR BIOLOGICS EVALUATION AND RESEARCH, Guidance for industry. Gene therapy clinical trials-observing participants for delayed adverse events. Draft guidance. 2005;WALDBY, C. and MITCHELL, R., “Tissue economies. Blood, organs and cell lines in late capitalism”, Duke University Press, Durham and London, 2006, viii+ 225p. WILLIAMS, D.W., “Tissue engineering: the multidisciplinary epitome of hope and despair.” In: Paton R, McNamara L, eds. Studies in Multidisciplinarity, Elsevier, 2006, 483-524. WILLIAMS, D.W., “ To engineer is to create: the link between engineering and regeneration”, Trends Biotechnol., 2006, 4. WILLIAMS, D.W., “A registry of tissue engineering Clinical trials”, Devicelink, 2006, http://www.devicelink.com/mdt/archive/06/06/001.html YOUNGNER, S.J., ANDERSON, M.W. and SCHAPIRO, R. (ed.), “Transplanting human tissue. Ethics, Policy and Practice”, Oxford University Press, Oxford, 2004, xiv + 216p.

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ALREADY PUBLISHED

H. NYS, et al., “Patient Rights in the EU – Czech Republic”, European Ethical-Legal Papers, N° 1, Leuven, 2006. H. NYS, et al., “Patient Right in the EU – Denmark”, European Ethical-Legal Papers, N° 2, Leuven, 2007. P. BORRY, et al., “Genetic testing and counselling. European Guidance", European Ethical-Legal Papers, N° 3, Leuven, 2007. H. NYS, “Removal of Organs in the EU, European Ethical-Legal Papers, N° 4, Leuven, 2007. H. NYS, et al., “Patient Rights in the EU – Estonia”, European Ethical-Legal Papers, N°5, Leuven, 2007. T. GOFFIN, et al., “Patient Rights in the EU – Greece”, European Ethical-Legal Papers, N°6, Leuven, 2007.

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