SAJBL Vol 8, No 2 (2015): Stem cell Supplement

ISSN 1999-7639

THE SOUTH AFRICAN JOURNAL OF

BIOETHICS & LAW August 2015 Vol. 8 No. 2 Supplement 1

Financial support for SAJBL is received from the Medical Protection Society.

SAJBL is published by the Health and Medical Publishing Group.

THE SOUTH AFRICAN JOURNAL OF

BIOETHICS & LAW

AUGUST 2015 Vol. 8 No. 2 Supplement 1

CONTENTS

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EDITORIALS The use of stem cells in research and therapies: Ethical, legal and social issues A Dhai SAJBL: Flagship special stem cell edition M S Pepper

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HUMAN TISSUE AND STEM CELL LEGISLATION Human tissue legislation in South Africa: Focus on stem cell research and therapy M S Pepper, M Nőthling Slabbert A global comparative overview of the legal regulation of stem cell research and therapy: Lessons for South Africa M Nőthling Slabbert, M S Pepper

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PLURIPOTENT STEM CELLS Legislation governing pluripotent stem cells in South Africa M S Pepper, C Gouveia, M Nőthling Slabbert Mitochondrial transfer: Ethical, legal and social implications in assisted reproduction A S Reznichenko, C Huyser, M S Pepper

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STEM CELL TOURISM Legal implications of translational promises of unproven stem cell therapy W M Botes, A Alessandrini Stem cell tourism in South Africa: A legal update M Nőthling Slabbert, M S Pepper, S Mahomed

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INFORMED CONSENT Towards guidelines for informed consent for prospective stem cell research J Greenberg, D C Smith, R J Burman, R Ballo, S H Kidson Informed consent in clinical trials using stem cells: Suggestions and points of attention from informed consent training workshops in Japan M Kusunose, F Nagamura, K Muto

RESEARCH 55 Biobanks and human health research: Balancing progress and protections

A Dhai, S Mahomed, I Sanne 60 Benefit sharing in health research

S Mahomed, I Sanne

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EDITOR Ames Dhai GUEST EDITOR Michael S Pepper CO-EDITOR David McQuoid-Mason EDITORIAL BOARD Kevin Behrens Alexandra Capron Peter Cleaton-Jones Liz Gwyther Mariana Kruger Willem Landman Leslie London Nhlanhla Mkhize Charles Ngwenya J P de V van Niekerk Daniel Wikler PUBLISHED BY THE HEALTH AND MEDICAL PUBLISHING GROUP (HMPG) CEO AND PUBLISHER Hannah Kikaya EDITOR-IN-CHIEF Janet Seggie MANAGING EDITOR Ingrid Nye EXECUTIVE EDITOR Bridget Farham TECHNICAL EDITORS Diane de Kock Emma Buchanan Paula van der Bijl PRODUCTION MANAGER Emma Jane Couzens DTP & DESIGN Carl Sampson ONLINE SUPPORT Gertrude Fani FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele Dr M Mbokota Dr G Wolvaardt Dr M R Abbas Mr G Steyn Mrs H Kikaya Dr M J Grootboom Prof. E L Mazwai Adv. Y Lemmer ISSN 1999-7639 Plagiarism is defined as the use of another’s work, words or ideas without attribution or permission, and representation of them as one’s own original work. Manuscripts containing plagiarism will not be considered for publication in the SAJBL. For more information on our plagiarism policy, please visit http://www.sajbl.org.za/ index.php/sajbl/about/editorialPolicies

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EDITORIAL

The use of stem cells in research and therapies: Ethical, legal and social issues

Ames Dhai Editor (amaboo.dhai@wits.ac.za) Ethical, legal and social issues associated with health research in general are multiple and complex. The complexity increases when research involves human tissues, and in particular stem cells as the trajectory of the latter will include scientific and technological advances not previously explored.

In April 2013 the South African Medical Research Council published a request for applications (RFA) for a new funding opportunity called the University Flagship Awards. These Awards are the largest medical research grants awarded by the MRC. After an initial internal selection process in the country's universities and science councils,

a rigorous external review process of the selected applications was undertaken. One of the successful applicants was Prof. Michael Pepper (guest editor of this issue), at the University of Pretoria. Utilising a multidisciplinary approach, from pure scientific to clinical, ethicoregulatory and social aspects, his proposal was centred on stem cells.

Accomplished scientists from diverse disciplines both in South Africa and abroad are involved in this project, which aims to contribute to the alleviation of the heavy burden of disease in South Africa through the translation of high-quality, high-impact research findings into practice and policy.

This issue is specific to the ethical, legal and social issues that arise in the context of stem cell research and therapies. Articles span not only the South African setting, but also the wider global situation. First authors of all the papers published in this issue, except for ‘Informed consent in clinical trials using stem cells: Suggestions and points of attention from informed consent training workshops in Japan’, are investigators in the Flagship Award. The issue, and most of the research published in this supplement, is the result of funding provided by the Medical Research Council of South Africa in terms of the MRC’s Flagships Awards Project SAMRC-RFA-UFSP-01-2013/ STEM CELLS.

SAJBL: Flagship special stem cell edition

Michael S Pepper Guest Editor From the perspective of medical and scientific research, South Africa is well placed through its many resources to make an important positive contribution to the global knowledge base and also to the improvement of the quality of life of its patients. Our focus is on stem cells and the potential impact their clinical translation will have on the lives of many South Africans.

The ethical, legal, and social issues (ELSI) related to stem cells are numerous and complex. Critical to the success of research and therapy in the stem cell field is a well-balanced legislative environment. Stem cell legislation in South Africa is governed principally by the National Health Act (No. 61 of 2003) and the Medicines and Related Substances Act (No. 101 of 1965). While this legislation and the associated regulations (promulgated in April 2012) provide for some of the requirements including ministerial authorisation, authorised institutions, patient informed consent, clinical trials, registration of new medicines (or biological medicines),

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anonymity, traceability, etc., there are a significant number of important areas in the field that are not adequately covered, and South Africa, like many other parts of the world, is being subjected to the problem of stem cell tourism.

In 2014 the South African Medical Research Council (SAMRC) awarded a University Flagship Award to the stem cell group based at the University of Pretoria (UP). The project involves scientists from diverse disciplines both in South Africa and abroad. The Flagship project entitled ‘Stem cell research and therapy – addressing South Africa’s disease burden’ aims to contribute to the alleviation of the heavy burden of disease in South Africa through the translation of high-quality, high-impact research findings into practice and policy.

Some of the objectives from an ELSI perspective are: • To critically evaluate existing legislation in South Africa dealing with human tissues and in particular stem cells.

• To compare stem cell legislation in South Africa to legislation in the European Union and the USA, and also in other developing nations.

• To propose legislation in areas where important gaps currently exist such as the use of autologous stem cells and the requirements relating to cells that have been manipulated ex vivo (including the notion of ‘minimally-manipulated’).

• To determine the presence and magnitude of stem cell tourism in South Africa and to assist the National Department of Health in establishing measures to halt this practice.

In order to achieve these objectives, and in collaboration with the South African Journal for Bioethics and Law, a call was issued in late

EDITORIAL 2014 for proposals for articles for a special issue on stem cells. The ten manuscripts published herein were chosen after a rigorous selection process, and represent, we believe, a relevant and balanced overview of many of the important stem cell issues facing patients, medical and legal practitioners, researchers and business.

The special edition has been divided into five sub-sections each with two articles. The first deals with human tissue and stem cell legislation both in South Africa and abroad. The second deals with pluripotent stem cells, which include embryonic and induced pluripotent stem cells. The third section deals with stem cell tourism and the fourth with informed consent. The fifth and final section deals with biobanks and also takes an in-depth look at the notion of benefit sharing.

In order to achieve the objective of reducing the heavy burden of disease currently being experienced in South Africa, particularly in the context of new and innovative therapies, it is critical that the legislative environment is robust to ensure patient safety and to prevent exploitation of emotionally vulnerable individuals. However, it is also necessary to ensure that the legislation is not restrictive with regard to investment into new technologies and the emergence of start-up biotechnology and other companies. We believe that by being directly involved in the stem cell field and with a keen interest in the legislation, we are well placed to assist the government and other entities to ensure the realisation of these objectives in a well-balanced legislative environment. The publication of this special edition will, we believe, make an important contribution towards achieving these objectives.

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LEGISLATION

Human tissue legislation in South Africa: Focus on stem cell research and therapy M S Pepper,1 MB ChB, PhD, MD; M Nőthling Slabbert,2 BA, BA Hons, MA, DLitt, LLB, LLD Department of Immunology, Institute for Cellular and Molecular Medicine, and SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, South Africa; Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Switzerland 2 Department of Jurisprudence, Faculty of Law, University of South Africa 1

Corresponding author: M S Pepper (Michael.pepper@up.ac.za)

The South African (SA) legislative framework follows a hierarchical structure aligned with the relevant level of government (national, provincial or local) responsible for applying and monitoring the legislation, with the overarching and progressive Constitution as the supreme law.

Delegated legislation (also known as secondary or subordinate legislation, e.g. regulations) ‘adds flesh’ to Acts of Parliament, or other forms of original legislation. The control and use of human tissue in South Africa is primarily governed by the National Health Act and relevant regulations, although other national acts, in differing degrees, are also relevant to this complex field. These include, among others, the Medicines and Related Substances Act, the Consumer Protection Act, the Children’s Act and the Inquest Act. Regulations generally only require ministerial and not parliamentary approval and are therefore (theoretically) easier to amend. In principle, the drafting of Acts should be preceded by policy documents, which contain broad foundational guidelines or a statement of intent in the area in question. Another useful source in the interpretation of legislation, albeit not officially recognised as legislation, is guidelines (sometimes referred to as standards), that may provide greater granularity than the regulations. Although neither policy documents nor guidelines are directly legally binding, a lack of compliance with the latter may have legal significance. In this article, the components of the hierarchical structure relevant to the legal regulation of human tissue in SA will be examined, with a specific focus on stem cell research and therapy. A critical analysis of the accuracy, relevance, redundancy and completeness (or lack thereof ) of these components will be provided. Furthermore, recommendations outlining the procedures that should be undertaken to remedy the inadequacies of the current legislative framework will be suggested. Given the welldefined structure of this framework and the relative youth of human tissue legislation in SA, the legislator has an opportunity to mirror the values and principles embodied in the Constitution by addressing these inconsistencies, and in the process develop a globally-applicable and appropriate legislative model in the fields of stem cell research and therapy.

S Afr J BL 2015:8(2 Suppl 1):4-11. DOI.10.7196/SAJBL.8008

Human tissue legislation is complex. It is characterised by an ever-changing landscape in which advances in science and medicine need to be accommodated.

A high degree of technical expertise is required to ensure that the legislation is accurate, appropriate and unambiguous.

However, it is generally accepted that the law has struggled to keep pace with advances in science and technology.[1] The legislative framework governing the control and use of human tissue has at its apex the Constitution of the Republic of South Africa, 1996, relevant statutes and regulations, as well as standards and guidelines. The legal force and status of each of these and the

Table 1. The legislative framework governing the control and use of human tissue

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Level

Legally-binding

Constitution

Yes

Human tissues

Policy

No

Limited

Act

Yes

Yes

Regulations

Yes

Incomplete

Guidelines standards

No

None officially

August 2015, Vol. 8, No. 2, Supplement 1 SAJBL

extent to which they have been developed in South Africa (SA) with regard to the regulation of human tissue are summarised in Table 1.

The development of legislation is preceded by a policy document detailing the objectives and expectations of the proposed legislation.

Stem cell research and therapy Stem cells are defined as undifferentiated cells capable of self-renewal that can differentiate into specialised cell types in response to appropriate environmental (e.g. chemical, mechanical) cues. There are several types of stem cells, which for the purpose of this discussion we will divide into pluripotent and adult. Pluripotent stem cells include embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, while adult stem cells include haematopoietic and mesenchymal stem cells (HSCs and MSCs).

Most other stem cell types can be included in this broad definition. Pepper, Gouveia and Slabbert will deal with pluripotent stem cells in detail in the article on pg. 23 of this special issue. A limited number of clinical trials involving pluripotent stem cells are underway, in which differentiated and specialised derivatives of these cells are being assessed.

With regard to adult stem cells, HSC transplantation is the only universally accepted and routinely applied form of stem cell therapy.

The potential for stem cells to be used in the treatment of a much broader spectrum of diseases is real, but hard to measure. This includes epidermal cells for skin defects and autologous cartilage

LEGISLATION implantation for articular cartilage defects. Clinical trials are underway to assess the use of stem cells in the treatment of heart disease.

Likewise, preclinical and early clinical trials have highlighted the potential of stem cells for the treatment of diabetes, spinal cord injury and other central nervous system disorders (e.g. cerebral palsy and Parkinson’s disease). Adult stem cells per se display very few complications, while the major potential risk associated with pluripotent cells is tumorigenicity.

There are several essential pillars to a successful cell therapy environment. These include a robust regulatory environment, quality assurance and accreditation. Also essential is an appropriate informed consent process, in which the benefits and potential side-effects of the therapy are clearly laid out. The legal requirements for tissue donation should also be clearly articulated to curtail possible trade and trafficking in human tissue.

What is the current situation in SA? Hematopoietic stem cell transplantation has been practised successfully in the country for several decades. Sources of stem cells mainly include bone marrow and peripheral blood, which may be autologous, or allogeneic. Umbilical cordblood-derived stem cells have also been used. SA also has a Bone Marrow Registry (SABMR)[2] that sources stem cells from unrelated voluntary donors for allogeneic transplantation. SA does not at present have a public cord-blood stem cell bank. In SA private cord-blood banking is offered by Netcells Biosciences and Cryo-Save South Africa. The difference between public and private banks is essentially the difference between an anonymous donation versus storage for private use: in the case of a public bank, cord blood is donated altruistically and is available for any histocompatible patient who needs an allogeneic transplant, while in the case of a private bank, the bank is paid to store cord-blood stem cells for autologous use or for use by next-of-kin. Private banks are contractually obliged to return the stored cells on request and at the bank’s expense, exclusively to the owner (or a contractually determined beneficiary).

Human tissue legislation – objectives Human tissue legislation broadly aims to protect the individual from harmful and unethical practices, while at the same time giving effect to the individual’s right to autonomy and self-determination as this relates to decisions regarding the use of his or her own stem cells.

The Constitution directs in section 39(2) that, when interpreting legislation, every court, tribunal or forum ‘must promote the spirit, purport or objects of the Bill of Rights’, which in essence refers to the promotion of the public interest. The legislative process should strive to further the goals and objectives of the Constitution, which includes the promotion of human rights. For example, all South Africans should be able to share in the benefits arising from advances in medical science in an equitable and sustainable manner.

In developing legislation, objectives should be realistic and every effort should be made to ensure simplicity and clarity. In the context of the regulation of human tissue, legislation should be enabling and not be unduly restrictive so as to avoid stifling basic and clinical research and biotechnological innovation. If legislation includes sanctions, these should be unambiguous and legally justified. Those affected by any legislative restriction or penalty should be aware of the limitations and the consequences of any transgressions.

In order to achieve all of the above, South African-specific objectives need to be combined with international best practice and the involvement of local professional societies needs to be encouraged.

The South African Constitution The Constitution of the Republic of South Africa, 1996, enshrines the values on which SA’s constitutional democracy is founded. Chapter 2 of the Constitution (the Bill of Rights) contains the fundamental rights and freedoms. These rights may be limited by section 36 of the Constitution and are therefore not absolute. However, some of the rights that are specifically relevant in the context of the regulation of human tissue are the right to equality (section 9); the right to human dignity (section 10); the right to life (section 11); the right to privacy (section 14); the right of a person to freedom and security, which includes the right to security in and control over one’s body and the right not to be subjected to medical or scientific experiments without informed consent (section 12); and the right of access to healthcare (section 27).

The following four principles, espoused by Beauchamp and Childress[3] provide a very useful framework for the consideration of medical ethics issues generally, namely: • Autonomy, which includes respecting the patient’s right to make decisions regarding her or his treatment. In this respect, consent always needs to be informed in the broadest sense with the patient being made aware of both the benefits and possible side-effects.

The importance of an adequate Materials Transfer Agreement cannot be overemphasised, particularly in a country in which discrimination and benefit sharing have not been adequately addressed. Both autonomy and self-determination are recognised in the provisions regarding the right to bodily and psychological integrity, the right to privacy and the right to life. Human dignity, inextricably linked to health and life as a constitutional value, informs the interpretation of all other rights.[4] • Beneficence, the moral foundation on which the medical profession rests, includes a consideration of the benefits of treatment against risks and costs. It is also critical that the therapy being applied has previously been shown to be of benefit in patients with a similar condition, preferably through the avenue of well-controlled and appropriately designed clinical trials. Beneficence finds expression in the provisions of the Constitution that relate to the right to life and the right of access to healthcare services (within the limits of available resources).

• Non-maleficence, which implies avoiding the causation of harm.

The harm should not be disproportionate to the benefits of the treatment. Early phase clinical trials (phases I and II) are required to establish the facts. This principle is expressed, for example, in the constitutional right not to be subjected to medical or scientific experiments without informed consent.

• Justice and fairness, which require that benefits, risks and costs be distributed fairly. In the SA context, distributive justice will ensure that all South Africans will benefit from cell-based therapy. The right to equality and the right of access to healthcare services embody these principles.

These four principles are not only aligned with the Constitution, but if observed, will promote the realisation of the rights articulated therein, in addition to assisting in deterring possible criminal and unprofessional conduct in the context of stem cell research and therapy.

The Acts Principally Chapter 8 of the National Health Act (NHA) 61 of 2003 governs the legal regulation of human tissues. The NHA has

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LEGISLATION repealed and replaced the Human Tissue Act 65 of 1983, which governed many areas of human tissue legislation but was clearly lacking with regard to more recent developments in the field.

Briefly, the National Health Act makes provision in Chapter 8 for control of the use of blood, blood products, tissue and gametes in humans. This includes provisions regulating, among others, the removal and use of tissue, blood, blood products or gametes from living persons and the transplantation of tissue from one living person to another. The Act also regulates payment in connection with the importation, acquisition or supply of tissue, blood, blood products or gametes, as well as the donation of human bodies and tissue from deceased persons. Chapter 8 furthermore provides for the allocation and use of human organs, as well as the purposes of the donation of the body, tissue, blood or blood products of deceased persons. The post-mortem examination of bodies, including the removal of tissue at post-mortem examinations and obtaining of tissue by institutions and persons are also regulated by the Act. In addition, not only is trade or trafficking in the human body or body parts prohibited in terms of section 60(4), as is the exploitation of the body as a commodity, but such conduct would also violate the right to human dignity reflected in the Constitution. The Medicines and Related Substances Control Act 101 of 1965 (Medicines Act) is more relevant to the clinical translation of stem cell therapy than the research component of stem cells, while the Children’s Act 38 of 2005, the Inquest Act 58 of 1959 and the Consumer Protection Act 68 of 2008 all have bearing on stem cell research and therapy in SA. The NHA was assented to by the President on 18 July 2004 and came into force on 2 May 2005. However, the main section dealing with human tissues, namely Chapter 8 entitled the ‘Control of use of blood, blood products, tissue and gametes in humans’, was only fully enacted as recently as 2 March 2012. As mentioned previously, matters pertaining to human tissues were previously legislated under the Human Tissue Act 65 of 1983, which was repealed with the enactment of the final sections of the NHA in 2012.[5] Chapter 8 of the NHA covers seven areas that are relevant to human tissues. These include: • Blood and blood products • Assisted reproductive technology • Cell-based therapy • Transplantation • DNA and genetic services • Tissue banks • Examination, allocation and disposal of human bodies and tissues.

‘Tissue’ is defined in section 1 of the NHA as ‘human tissue, and includes flesh, bone, a gland, an organ, skin, bone marrow or body fluid, but excludes blood or a gamete’. An organ is defined in the same section as ‘any part of the human body adapted by its structure to perform any particular vital function, including the eye and its accessories’. Suggested alternatives to these definitions are provided in Table 2.

With regard to human cloning, the manipulation of any genetic material for the purpose of reproductive cloning of a human being is prohibited in terms of section 57(1) of the NHA, read together with section 57(6)(a). Cloning for therapeutic purposes is provided for in section 57(2) of the Act, read together with section 57(6)(b).

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These definitions (i.e. ‘reproductive cloning of a human being’ and ‘therapeutic cloning’) are however problematic; alternatives are provided in Table 3. A person contravening or failing to comply with this section is guilty of an offence and is liable, on conviction, to a fine or to imprisonment for a period not exceeding 5 years or to both a fine and such imprisonment (section 57(5)).

Research on stem cells and zygotes which are not more than 14 days old may in terms of section 57(4) of the NHA only be conducted with the permission of the Minister and under certain conditions, namely that the research shall be documented and prior consent be obtained from the donor of such stem cells or zygotes.

Section 56 of the NHA (‘Use of tissue, blood, blood products or gametes removed or withdrawn from living persons’) provides that that the removal or withdrawal of stem cells (excluding umbilical cord progenitor cells) from a living person for medical or dental purposes requires ministerial authorisation. Specific restrictions regarding the removal of tissue, blood, blood products or gametes from living persons are found in section 56(2), which states as follows: ‘(2) (a) Subject to paragraph (b), the following tissue, blood, blood products or gametes may not be removed or withdrawn from a living person for any purpose contemplated in subsection (1): (i) tissue, blood, a blood product or a gamete from a person who is mentally ill within the meaning of the Mental Health Care Act, 2002 (Act no. 17 of 2002); (ii) tissue which is not replaceable by natural processes from a person younger than 18 years; (iii) a gamete from a person younger than 18 years; or (iv) placenta, embryonic or foetal tissue, stem cells and umbilical cord, excluding umbilical cord progenitor cells. (b) The Minister may authorise the removal or withdrawal of tissue, blood, a blood product or gametes contemplated in paragraph (a) and may impose any condition which may be necessary in respect of such removal or withdrawal.’

This implies that HSC transplantation, which has been practised for several decades in SA, requires ministerial authorisation, as will all future applications of stem cell therapy requiring removal or withdrawal of stem cells from a living person. The exception appears to be umbilical cord progenitor cells, which implies that other cells harvested from cord blood (i.e. earlier primitive stem cells that are not progenitors and non-haematopoietic stem cells) will also require ministerial authorisation. The legislator’s reason for making this distinction is not apparent. On the other hand, no mention is made of the requirement for ministerial approval in the Regulations Relating to the Use of Human Biological Material, which provide that biological material – which includes progenitor stem cells[6] – may be removed or withdrawn from living adult persons with their informed consent.[7] It is suggested that section 56(2)(a)(iv) above be changed to refer only to ‘embryonic or fetal tissue’.

In addition to Chapter 8, several important areas are covered by Chapter 9 of the NHA which deals with ‘National Health Research and Information’. Section 71, for example, entitled ‘Research on or experimentation with human subjects’, states that all research conducted on minors (e.g. persons younger than 18 years) for non-therapeutic purposes requires ministerial authorisation (section 71(3)), whereas in the instance of research for therapeutic purposes, ministerial authorisation is apparently not required

LEGISLATION Table 2. Definitions from the National Health Act and Regulations thereto relating to tissues and organs Name

Definition

Source

Comment / proposal

tissue

human tissue, and includes flesh, bone, a gland, an organ, skin, bone marrow or body fluid, but excludes blood or a gamete

National Health Act (No. 61 of 2003)

Proposal – replace with: human tissue, and includes skin and appendages, flesh, bone, bone marrow, body fluid, a gland, an organ, but excludes blood, gametes and stem cells

a functional group of cells. The term is used collectively in Regulations to indicate both cells and tissue

Regulations Relating to Tissue Banks (No. R. 182)

organ

any part of the human body adapted by its structure to perform any particular vital function, including the eye and its accessories, but does not include skin and appendages, flesh, bone, bone marrow, body fluid, blood or a gamete

National Health Act (No. 61 of 2003)

biological material

material from a human being including DNA, RNA, blastomeres, polar bodies, cultured cells, embryos, gametes, progenitor stem cells, small tissue biopsies and growth factors from the same

Regulations Relating to the Use of Human Biological Material (No. R. 177)

biological samples

no definition in the current legislation

body specimen

any body sample which can be tested to determine the presence or absence of HIV infection

Regulations regarding the Rendering of Clinical Forensic Medicine Services (No. R. 176)

body fluid

any body substance which may contain HIV or any other sexually transmissible infection, but does not include saliva, tears or perspiration

Regulations regarding the Rendering of Clinical Forensic Medicine Services (No. R. 176)

substance

tissue, blood, blood product or gamete

Regulations Relating to the Import and Export of Human Tissue, Blood, Blood Products, Cultured Cells, Stem Cells, Embryos, Foetal Tissue, Zygotes and Gametes. (No. R. 181)

to traffic

no definition in the current legislation

Proposal – replace with: any part of the human body adapted by its structure to perform any particular vital function, including the eye and its accessories, but does not include skin and appendages, flesh, bone, bone marrow, body fluid, blood, a gamete or stem cells

Proposal: samples derived from tissue and blood including cells, DNA, RNA and protein

(section 71(2)), but only the consent of the parent or guardian, or the relevant child if he or she is capable of understanding. The rationale behind the requirement for ministerial authorisation where research or experimentation is to be conducted on a minor for non-therapeutic purposes (not benefiting the specific minor), but not for therapeutic purposes, is unclear. The Minister may not authorise such research for non-therapeutic purposes involving a minor if, among others, the research poses a ‘significant risk’ to the

Proposal: to recruit, transport, transfer, harbour or receive tissue by means of threat, coercion, abduction, fraud, deception or the abuse of power of a position of vulnerability, or to give or receive payments or benefits to achieve the transfer of tissue

health of the minor, or ‘some risk’, though there is the likelihood of ‘some benefit’ to the minor (section 71(3)(b)). Paradoxically, it would seem that ministerial authorisation for the latter would be important. The purpose of this is clearly to protect minors from unscrupulous research practices, but in the absence of a definition of what ‘significant risk’ or ‘some risk’ are, which differ from the requirements stated in the national ethics guidelines,[8] this adds more confusion.[9]

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LEGISLATION Table 3. Definitions from the National Health Act and Regulations thereto relating to stem cells Name

Definition

Source

Comment /proposal

cell

the basic structural and functional unit in people and all living things and is a small container of chemical and water wrapped in a membrane

Regulations Relating to the Artificial Fertilisation of Persons (No. R. 175)

This definition is not appropriate

the smallest structural and functional unit of an organism, consisting of cytoplasm and a nucleus enclosed in a membrane in living things

Regulations Relating to the Use of Human Biological Material (No. R. 177)

cells that have been grown outside the body

Regulations Relating to the Use of Human Biological Material (No. R. 177)

any human cells grown in vitro supported by suitable growth media

Regulations Relating to the Import and Export of Human Tissue, Blood, Blood Products, Cultured Cells, Stem Cells, Embryos, Foetal Tissue, Zygotes and Tametes (No. R. 181)

a cell that has both the capacity to self-renew as well as to differentiate into mature, specialised cells

Regulations Relating to the Use of Human Biological Material (No. R. 177)

a cell that has both the capacity to self-renew as well as to differentiate into mature, specialised cells

Regulations Relating to Blood and Blood Products (No. R. 179)

any embryonic stem cell or circulating, bone marrow, umbilical cord or haemopoietic progenitor cell, or any cell that is capable of replicating or proliferating and giving rise to a differentiated cell

Regulations Relating to the Import and Export of Human Tissue, Blood, Blood Products, Cultured Cells, Stem Cells, Embryos, Foetal Tissue, Zygotes and Gametes (No. R. 181)

cells that have both the capacity to self-regenerate as well as to differentiate into mature specialised cells

Regulations Relating to Stem Cell Banks (No. R. 183)

progenitor cells

stem cells which give rise to a distinct stem cell line

Regulations Relating to the Use of Human Biological Material (No. R. 177)

umbilical cord blood stem cell

stem cells found in umbilical cord blood

Regulations Relating to the Use of Human Biological Material (No. R. 177)

embryonic stem cell

any cell from the 30-200 inner cell mass of the blastocyst

Regulations Relating to the Use of Human Biological Material (No. R. 177)

transgenic cells

cells derived from a species other than human

Regulations Relating to the Use of Human Biological Material (No. R. 177)

Definition incorrect Proposal: xenogeneic to replace “transgenic�

reproductive cloning of a human being

the manipulation of genetic material in order to achieve the reproduction of a human being and includes nuclear transfer or embryo splitting for such purpose

National Health Act (No. 61 of 2003) Section 57(6)(a)

Proposal – replace with: the manipulation of cells, gametes, zygotes or embryos or genetic material derived therefrom in order to achieve the reproduction of a human being, and includes but is not limited to nuclear transfer and embryo splitting

cultured cells

stem cell

Continued ...

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LEGISLATION Table 3. (continued) Definitions from the National Health Act and Regulations thereto relating to stem cells Name

Definition

Source

Comment /proposal

therapeutic cloning

the manipulation of genetic material from either adult, zygotic or embryonic cells in order to alter, for therapeutic purposes, the function of cells or tissues

National Health Act (No. 61 of 2003) Section 57(6)(b)

Definition should include somatic cell nuclear transfer – for example, replace with: use of embryonic stem cells, which are derived from a blastocyst following somatic cell nuclear transfer, for therapeutic purposes

Table 4 Regulations published in Government Gazette No. 35099 on 2 March 2012 Regulation No.

Title

Pages

No. R. 175

Regulations Relating to Artificial Fertilisation of Persons

GG 35099 pages 3-21

No. R. 176

Regulations Regarding the Rendering of Clinical Forensic Medicine Services

GG 35099 pages 22-30

No. R. 177

Regulations Relating to the Use of Human Biological Material

GG 35099 pages 31-38

No. R. 179

Regulations Relating to Blood and Blood Products

GG 35099 pages 62-74

No. R. 180

Regulations Regarding the General Control of Human Bodies, Tissue, Blood, Blood Products and Gametes

GG 35099 pages 75-96

No. R. 181

Regulations Relating to the Import and Export of Human Tissue, Blood, Blood Products, Cultured Cells, Stem Cells, Embryos, Foetal Tissue, Zygotes and Gametes.

GG 35099 pages 97-124

No. R. 182

Regulations Relating to Tissue Banks

GG 35099 pages 125-141

No. R. 183

Regulations Relating to Stem Cell Banks

GG 35099 pages 142-158

Regulations Various sets of regulations relating to Chapter 8 of the NHA came into effect on 2 March 2012 (Table 4). These include regulations relating to the general control of human bodies, tissue, blood, blood products and gametes;[10] the use of human biological material;[11] blood and blood products;[12] import and export of human tissue, blood, blood products, cultured cells, stem cells, embryos, fetal tissue, zygotes and gametes;[13] stem cell banks[14] and tissue banks.[15] With regard to some of these sets of regulations that relate to human tissue, there is a degree of redundancy and overlap. Definitions, for example, are not harmonised, both between different regulations and relative to the NHA. In addition, there are at present no regulations regarding cell-based therapy, bio-banks or transplantation.

With regard to definitions, a cell is defined in Regulations Relating to the Artificial Fertilisation of Persons as ‘the basic structural and functional unit in people and all living things and is a small container of chemical and water wrapped in a membrane’ (Table 3). This definition is clearly wanting for detail, which is necessary in the modern setting of highly sophisticated technology. On the other hand, the regulations on the use of human biological material defines a cell as ‘the smallest structural and functional unit of an organism, consisting of cytoplasm and a nucleus enclosed in a membrane in living things’, which is more appropriate.

Transgenic cells are defined in the Regulations Relating to the Use of Human Biological Material as cells being ‘derived from a species other than human’. The universally accepted definition of cells derived from a species other than human is ‘xenogeneic’. For example,

one source[16] defines xenogeneic as ‘derived or obtained from an organism of a different species, as a tissue graft’.

Transgenic on the other hand means an organism whose genome has been altered by the transfer of a gene or genes through recombinant DNA techniques from another species or breed using recombinant DNA techniques, e.g. transgenic mice.[17] It is understood that the foreign genes are in the transgenic animal’s germ-cell DNA and so can be transmitted from one generation to the next.[18] Clearly this and other frankly incorrect definitions require urgent amendment.

Guidelines and standards With regard to guidelines and standards, none have been officially published or endorsed by the National Department of Health in the human tissue field. As a result and in response to the need to provide clarity to professionals working in these fields, several professional bodies have established their own guidelines. These bodies are listed in Table 5.

It should be noted, however, that national standards for cellular therapy product collection, processing, storage and distribution have been drafted and will hopefully be published in the near future.

These standards do not include stem cell therapy per se, which would for now need to be covered in SA by the South African Stem Cell Transplantation Society standards. It is important that the drafting of all guidelines and standards be done in close alignment with national professional bodies, as well as international bodies such as the Foundation for the Accreditation of Cellular Therapy,[19] the Joint

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LEGISLATION Table 5. Professional Bodies: Human tissues Area

Professional body

Guidelines

Transplantation

Southern African Transplantation Society (SATS)

Yes http://www.sats.org.za/Guidelines.asp

Assisted reproductive technology

Southern African Society of Reproductive Medicine and Gynaecological Endoscopy (SASREG)

Yes http://www.fertilitysa.org.za/TreatmentGuidelines/ ReproductiveMedicine.asp

Blood and blood products

National Blood Committee (not in operation since 2008)

Yes SANBS and WPBTS websites & other

Cell-based therapy

South African Stem Cell Transplantation Society (SASCTS)

Yes; none on website http://www.stemcell.org.za/index.htm

Genetic Services

Southern African Society of Human Genetics (SAHGS)

Yes http://www.sashg.org/documents.htm

Tissue banks

South African Tissue Bank Association (SATiBA)

Newly formed http://www.satiba.org.za

Forensic pathology and medicine

National Forensic Pathology Services Committee

Yes No website

National Clinical Forensic Committee

In progress

Accreditation Committee of the International Society for Cellular Therapy (ISCT) and the European Society for Blood and Marrow Transplantation (EBMT)[20] and the American Association of Blood Banks.[21]

Economic considerations Section 60 of the NHA, titled ‘Payment in connection with the importation, acquisition or supply of tissue, blood, blood products or gametes’ stipulates the following: ‘(1) No person, except(a) a hospital or an institution contemplated in section 58(l)(a), a person or an institution contemplated in section 63 and an authorised institution or, in the case of tissue or gametes imported or exported in the manner provided for in the regulations, the importer or exporter concerned, may receive payment in respect of the acquisition, supply, importation or export of any tissue or gamete for or to another person for any of the purposes contemplated in section 56 or 64; (b) a person or an institution contemplated in section 63 or an authorized institution, may receive any payment in respect of the importation, export or acquisition for the supply to another person of blood or a blood product.

(2) The amount of payment contemplated in subsection (1) may not exceed an amount which is reasonably required to cover the costs involved in the importation, export, acquisition or supply of the tissue, gamete, blood or blood product in question.

(3) This section does not prevent a health care provider registered with a statutory health professional council from receiving remuneration for any professional service rendered by him or her.

(4) It is an offence for a person(a) who has donated tissue, a gamete, blood or a blood product to receive any form of financial or other reward for such donation, except for the reimbursement of reasonable costs incurred by him or her to provide such donation; and (b) to sell or trade in tissue, gametes, blood or blood products, except as provided for in this Chapter.

(5) Any person convicted of an offence in terms of subsection (4) is liable on conviction to a fine or to imprisonment for a period not exceeding five years or to both a fine and such imprisonment.’

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Any discussion on human tissue legislation (and in particular stem cells) needs to make a distinction between activities that involve altruistic donation of human material and those that result in commercial gain. Any commercial activity directly involving human material (including stem cells) that is provided on an altruistic basis by a voluntary donor should be run on a not-forprofit cost recovery basis with publicly accessible accountability of how resources are managed. Other activities that involve human stem cells directly or indirectly and that are not based on the principle of an altruistic donation should be permitted to run on a for-profit basis. This includes storage and manipulation of stem cells for individuals who pay for the service on a fee-for-service basis, as well as all related activities including but not limited to the development and manufacture of materials for tissue culture (equipment, plastic ware, reagents including growth factors) and medical devices (including those required for stem cell harvesting and purification). It is important to note that the NHA prohibits the sale of and trade in stem cells, as this would be tantamount to ‘organ trafficking’ even though a stem cell(s) is not an organ per se.

Furthermore, an authorised institution may only receive payment in respect of the acquisition, supply, importation or export of stem cells.

Although it is clear that a public cord-blood bank in which stem cells are altruistically donated must be a not-for-profit company run on the basis of cost-recovery, the indiscriminate application across the board of a not-for-profit rule in all matters pertaining to human tissues and stem cells, in particular, would severely stifle the rollout of stem cell therapies and related research in SA. The cell therapy industry is still in its infancy in this country, and preventing the establishment of for-profit companies would stifle the implementation of new cell therapy technologies as well as all future research activity into stem cells in the biotechnology sector. The latter is emphasised in the Bioeconomy strategy released in 2014 by the Department of Science and Technology.[22] The therapeutic promise of stem cells has driven huge investment globally into the cell therapy industry. Without this investment, and the return it promises to bring to its investors, progress in the field would be significantly stunted.

LEGISLATION Conclusion Legislation in its broadest sense should be seen as a permanent workin-progress requiring ongoing review. The importance of feedback from all sectors concerned including patients and their healthcare providers cannot be overemphasised.

Legislation in its broadest sense is needed: • To ensure that pre-clinical studies and well controlled clinical trials have been conducted prior to introduction of cells into patients: • to ensure that the purported therapeutic effect is real • to ensure that there are no serious side effects • To ensure that work involving material that will be (re)introduced into patients is conducted in an accredited institution under strictly controlled conditions.

The absence of appropriate legislation: • Permits (and even encourages) the emergence of medically unsound and unethical practices that may be associated with the exploitation of emotionally vulnerable patients.

• Dissuades the transfer into SA of much-needed skilled individuals, intellectual property and foreign investment in the cell-therapy field.

In SA we have ‘need’ from the perspective of the patient, ‘ability’ from the perspective of the medical, scientific and business communities, and ‘material’ both from a research and therapeutic perspective.

Legislation in SA in the human tissue field, and in stem cells in par­ ticular, is still in its infancy. This provides healthcare professionals and researchers with an opportunity to assist the legislator in drafting legislation that is both modern and appropriate to the diverse needs of the SA population. However, while legislation is necessary to protect patients and their healthcare providers, it should not be stifling or obstructive.

With regard to clinical trials, these need to be registered with the Medicines Control Council (MCC) and would include any form of therapy that is unproven or experimental in nature. Protocols need to be examined by a registered institutional ethics committee (peer reviewed). Finally, patients should not have to pay for treatments that are unproven or experimental.

Based on the broad outline provided above and in mapping out the process ahead, it is recommended that: • An oversight and coordinating committee be established, which includes government, academia and the private sector, to work with groups in each of the seven areas delineated above together with the legislator, to constantly monitor new developments in order to be able to be agile in response thereto.

• The current legislation be revised to close regulatory gaps, remove inaccuracies and redundancy and to ensure that all legislation is harmonised.

Funding: This research and the publication thereof is the result of funding provided by the South African Medical Research Council in terms of the MRC’s Flagship Award Project SAMRC-RFA-UFSP-01-2013/STEM CELLS.

References 1. Laurie G, Harmon SHE. Through the Thicket and Across the Divide: Successfully Navigating the Regulatory Landscape in Life Sciences Research. In: Cloatre E, Pickersgill M, eds. Knowledge, Technology and the Law. Oxon: Routledge, 2015:119-136.

2. South African Bone Marrow Registry. http://www.sabmr.co.za/ (accessed 6 April 2015).

3. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. 5th edition. Oxford: Oxford University Press, 2001.

4. Dawood v. Minister of Home Affairs 2000 10 SA 997 (C) 5. Republic of South Africa. Proclamation No. 11. Government Gazette 35081, 27 February 2012.

6. Republic of South Africa. Regulations Relating to the Use of Human Biological Material. Government Gazette 35099, 2 March 2012, regulation 1.

7. Republic of South Africa. Regulations Relating to the Use of Human Biological Material. Government Gazette 35099, 2 March 2012, regulation 2.

8. Republic of South Africa. Ethics in Health Research: Principles, Structures and Processes. Pretoria: Department of Health. 2004. http://www.mrc.ac.za/ethics/ DOHEthics.pdf (accessed 31 March 2015).

9. Nienaber A. The statutory regulation of children’s participation in HIV clinicalrelated HIV research: More questions than answers. Tydskrif vir die Hedendaagse Romeins-Hollandse Reg 2008;71:672-676.

10. Republic of South Africa. National Health Act. Regulations GN R180. Government Gazette 35099, 2 March 2012.

11. Republic of South Africa. National Health Act. Regulations GN R177. Government Gazette 35099, 2 March 2012.

12. Republic of South Africa. National Health Act. Regulations GN R 179. Government Gazette 35099, 12 March 2012.

13. Republic of South Africa. National Health Act. Regulations GN R181. Government Gazette 35099, 2 March 2012.

14. Republic of South Africa. National Health Act. Regulations GN R183. Government Gazette 35099, 2 March 2012.

15. Republic of South Africa. National Health Act. Regulations GN R 182. Government Gazette 35099, 2 March 2012.

16. Definition of “xenogeneic”. The American Heritage® Dictionary of the English Language, 5th edition Copyright © 2013 by Houghton Mifflin Harcourt Publishing Company.

Definition of “xenogeneic”. Published by Houghton Mifflin Harcourt Publishing Company. http://medical.yourdictionary.com/xenogeneic (accessed 6 April 2015).

17. Biology Online. Definition of “transgenic”. Biology Online. http://www.biologyonline.org/dictionary/Transgenic (accessed 6 April 2015).

18. MedicineNet.com. http://www.medterms.com/script/main/art.asp?articlekey=11295 (accessed 6 April 2015).

19. Foundation of the Accreditation of Cellular Therapy. http://www.factwebsite.org/ (accessed 6 April 2015).

20. Joint Accreditation Committee ISCT EBMT. http://www.jacie.org/ (accessed 6 April 2015) 21. American Association of Blood Banks. http://www.aabb.org/Pages/default.aspx (accessed 6 April 2015).

22. Republic of South Africa. Bioeconomy Strategy. Pretoria: Department of Science and Technology, 2014. http://www.pub.ac.za/files/Bioeconomy%20Strategy.pdf (accessed 6 April 2015).

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LEGISLATION

A global comparative overview of the legal regulation of stem cell research and therapy: Lessons for South Africa M Nöthling Slabbert,1 BA, BA Hons, MA, DLitt, LLB, LLD; M S Pepper,2 MB ChB, PhD, MD Department of Jurisprudence, School of Law, University of South Africa, Pretoria, South Africa Department of Immunology, Faculty of Health Sciences; Institute for Cellular and Molecular Medicine and MRC Extramural Unit for Stem Cell Research and Therapy, University of Pretoria, South Africa; Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Switzerland 1 2

Corresponding author: M Nöthling Slabbert (slabbmn@unisa.ac.za)

Stem cell research and its potential translation to regenerative medicine, tissue engineering and cell and gene therapy, have led to controversy and debates similar to the calls nearly 25 years ago for a ban involving recombinant DNA. Global legislative efforts in this field have been characterised by many legal, ethical and practical challenges, stemming from conflicting views regarding human embryonic research and cloning. National policy and regulatory developments have primarily been shaped by different understandings of relevant scientific objectives, as well as those relating to the moral and legal status of the human embryo, which have been used to justify or limit a range of permissible activities. Legal obscurity in this field, a consequence of inconsistent or vague legislative responses at a national and international level, leads to negative results, which include, among others, ethical violations; lack of collaboration and co-operation among researchers across national borders; stunted scientific progress; lack of public trust in stem cell research; proliferation of untested ‘stem cell therapies’; and safety issues. The purpose of this article is to explore the legal regulation of stem cell research and therapy globally, by comparing the permissibility of specific stem cell research activities in 35 selected jurisdictions, followed by a comparison of the regulatory approaches with regard to stem cell-based products in the European Union and the USA. A clearer understanding of the global regulatory framework will assist in formulating more effective legal responses at a national level and in navigating the uncertainties and risks associated with this complex and evolving scientific field.

S Afri J BL 2015;8(2 Suppl 1):12-22. DOI:10.7196/SAJBL.8004

Few advances in medical research have generated as much interest and controversy as those relating to stem cell research and its potential applications in cell and gene therapy, regenerative medicine and tissue engineering. Recent techniques involving induced pluripotent stem cells (iPSCs) and human somatic cell nuclear transfer (SCNT) have raised new ethical and legal questions. The predominant early focus on an ‘embryo-centric’ approach in this field is slowly being overtaken by an approach focused on the globalisation of research and a concomitant need for ‘policy interoperability’.[1] Globally, policies and legislation regulating these developments are complex and varied, both within and between jurisdictions, described by some authors as ‘a patchwork of patchworks’.[2] In addition to variation in national laws and policies with regard to biomedical research and the development of therapeutic applications, variation also exists with regard to other related activities, such as research funding, normative and ethical principles and standards, governance mechanisms, quality assurance and access to stem cell material and data.[3] The regulatory environment is also deeply influenced by social, religious, cultural, economic, historical, ideological and political factors. Competing interests and values promoted and propagated by various agents from, among others, the scientific community, political parties, consumer organisations, interest groups (patient groups, religious organisations and pro-life organisations), the media and the general public, are also relevant.[4] Moral perceptions regarding the human embryo have shaped and informed substantive requirements

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and procedural safeguards regarding the use of human embryonic stem cells (hESCs) in many jurisdictions.[5] National policy development in this field is guided by international and regional instruments, guidelines and regulations that span biomedical research and related activities, adding a further layer of complexity. The United Nations Educational, Scientific and Cultural Organisation (UNESCO), Council of Europe and the EU have all addressed aspects of stem cell research and its clinical applications through various reports, treaties, resolutions, declarations and guidelines. Guidelines and recommendations by international organisations, such as the Council for International Organisations of Medical Science (CIOMS), the Hinxton Group, the International Consortium of Stem Cell Networks (ICSCN), the International Stem Cell Forum (ISCF) and the International Society for Stem Cell Research (ISSCR) are an instructive resource for policymakers. Nonetheless, human stem cell research, which involves the embryo and its clinical translation, remains a matter for national policy and lawmakers.

The impact of conflicting regulatory regimens is manifold and may affect, among others, the conduct of research, efficiency, collaboration, the clinical translation and commercialisation[6] of research.[3] Although regulatory variation is a natural consequence of heterogeneous contexts, unintended and unforeseen consequences may arise in areas where there are legal regulatory lacunae. One example is the need to balance innovative therapies with rigorous oversight and regulation in the exploitation of vulnerable patients through unproven and potentially harmful stem cell treatments

LEGISLATION in jurisdictions where the regulatory frameworks are ineffective or ambiguous.[7] The most common response to policy variance is a call for the development of harmonised legal and ethical standards.[1] A clearer understanding of the comparative global regulatory framework will assist in determining the scope of policy convergence or consistency that is required in order to navigate more efficient and ethical research and research collaboration in this field, as well as identify strategies to address these differences that may impede scientific progress and innovation.[2] It will also enable specific areas in the field to be harmonised, which could lead to improved policy interoperability.[2] Improved policy interoperability is possible when harmonisation of regulatory approaches is the focus (which doesn’t require similarity but rather compatibility),[8] instead of standardisation (which focuses on uniformity of approaches).[1] The purpose of this article is hence to explore the international legal regulatory framework by comparing selected national approaches toward human stem cell research and therapy by focusing on restrictions or permissions with regard to specific research activities.

The different national approaches are best understood in terms of a continuum with the most liberal and permissive regulatory regimens at one end (e.g. those that permit embryo research and the derivation of hESC from various sources and technologies, such as SCNT) and those that prohibit embryo research and related activities (e.g. the use of excess IVF embryos in hESC research) at the other. Surprisingly, jurisdictions with common political, legal, cultural and religious contexts may have very different policy approaches with regard to hESC research.[2] On a global front, the development of therapeutic stem cell applications, similar to that of stem cell research, is likewise characterised by legal uncertainty, and regulatory frameworks are under revision to cater for the unique challenges posed by translational stem cell research, which include efforts to harmonise guidelines relating to safety, efficacy, quality and the development of common technical requirements.

The comparisons drawn in this paper will assist in guiding future legislative developments in the fields of stem cell research and its clinical translation in South Africa.

Ethical issues

Moral status of human embryo The moral and legal status of the human embryo has always been clouded in controversy. A recent study that explored public perceptions regarding the moral status of the human embryo in nine European countries is no exception. Statements describing the embryo as a cluster of cells (e.g. the relative majority view in Denmark and the UK) were contrasted to others that accord the human embryo the same moral status as other human beings (more prevalent in Austria, Germany, Poland, and Italy).[9] Moral views on the human embryo are informed by the specific significance that persons attach to different stages of human embryonic development [10] such as fertilisation, when the primitive streak develops, when the fetal heart begins to beat, when mental functioning of the fetus commences, when the fetus becomes viable outside the womb, sustained with the help of technology, or when the child is born and able to breathe independently.[11] These moral perceptions may explicitly or implicitly influence views regarding

the possible uses and creation of human embryos for research purposes, and ultimately reflect society’s understanding of, trust in and expectations and reservations regarding scientific advances in this field. These important embryonic developmental milestones may perhaps not be useful in answering the question of when the law should recognise the embryo or fetus as a legal person to whom the full panoply of civil or constitutional rights should apply, but become relevant when demarcation lines are drawn for research activities involving the human embryo. For example, many jurisdictions agree on a 14-day limit following fertilisation, after which embryos may not be permitted to develop further in vitro.[10] An embryo beyond 14 days’ development is unlikely to implant in a woman’s womb.

The ambivalence regarding the embryo is reflected in an array of definitions across jurisdictions, with some defining the human embryo in relation to a specific time of embryonic development (e.g. eight weeks from the moment of conception, e.g. South Africa,[12] Australia,[13] India[14] and Singapore[15]), others stating its definitions in broad time frames (e.g. a ‘fertilised ovum at all stages of development’, e.g. Iceland, Estonia, UK, Finland and South Korea), and those that avoid references to gestational development, focusing instead on the capacity of the embryo to develop into a human being (e.g. New Zealand, Belgium, Japan and Germany).[16] In a ruling on 18 December 2014,[17] the Court of Justice of the EU clarified the status of embryos created through parthenogenesis (having only one set of DNA and unable to develop into human beings) by confirming that these parthenotes are excluded from the definition of a ‘human embryo’ as contained in Directive 98/44/ EC of 6 July 1999 of the European Parliament and Council on the legal protection of biotechnological inventions, and are hence patentable.[18] The hESC research has been regarded as ethically controversial by many because it is associated with the destruction of the human embryo i.e. when pluripotent stem cell lines are derived from the inner cell mass (ICM) of the 5 to 7-day-old pre-embryo or blastocyst.

The issue at stake, referred to above, is whether the embryo is merely a clump of cells or whether its (developmental) potential to become a human being bestows on it all the qualities and characteristics associated with human personhood (and consequently legal protection as a legal subject). The answers to these questions will determine the limits on the research activities that may be morally (and legally) permitted with regard to human embryos. Secondly, the source of these human embryos or hESCs is also relevant.

For example, in the case of embryos, were they created solely for research purposes or were they excess embryos left over after in vitro fertilisation? If not used and destined to be discarded in any event, would it be morally justifiable to use them in medical research aimed at ultimately benefiting the greater collective? Many jurisdictions insist on the destruction of human embryos used for research purposes, before 14 days of development (time at which the primitive streak appears).

The human embryo is not the only source of pluripotent stem cells. Pluripotent stem cells can also be derived from oocytes using specific techniques, such as SCNT. However, this process also requires development to the blastocyst phase in order to harvest ICM cells for creating ES cells. With regard to oocyte donation for research, this carries specific medical risks when the oocytes are retrieved. In addition, ethical concerns arise relating to the donation of oocytes

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LEGISLATION for research, as well as human reproduction and the protection of the reproductive interests of women undergoing infertility treatment.[19] Compliance with research governance requirements, informed consent procedures, as well as issues revolving around reimbursement or payment of gamete or embryo donors, is a key ethical consideration.[8]

Reproductive and therapeutic cloning The creation of stem cells through SCNT is another contested issue.

This procedure, which entails the removal of nuclear DNA from an unfertilised oocyte and replacing the removed DNA with the nuclear DNA from a somatic donor cell, was successfully carried out for the first time using human cells in 2013.[20] The reprogrammed oocyte containing the replaced DNA (genetically identical to the DNA of the donor) is stimulated to divide and develop into a blastocyst from which hESCs are harvested to create a stem cell line genetically identical to that of the cell donor. This technique allows researchers to develop genetically identical or compatible tissue for successful autologous tissue transplantation procedures. SCNT is controversial for two reasons. First, the harvesting of ICM cells from the blastocyst to create ES cells, and second because it may lead on to ‘cloning’ or the reproduction of a genetically identical organism. The intentional creation of embryos using this technique in humans (but not in domestic animals) is condemned for a number of reasons, namely that it diminishes human individuality and integrity, impacts on the freedom, identity and dignity of the human person (in the sense that multiple identical copies of the same DNA are possible), as well as human reproductive autonomy (e.g. that an embryo is created with only one genetic parent to which the embryo would be asymmetrically and genetically identical). Cloning furthermore raises the prospect of eugenics, for example the creation of offspring with certain desired and genetically enhanced characteristics, which will take society beyond therapy into very dangerous and unchartered terrain. These concerns raise vexing questions that are fundamental to our understanding of humanity, human identity, and inviolability of the human person, human reproduction and human dignity.

Strong opposition globally to cloning led to a world-wide ban on reproductive cloning in humans,[21] and as a consequence has cast a shadow on the use of SCNT, without distinguishing between ‘therapeutic cloning’ and ‘reproductive cloning’. As a technique, SCNT may produce a cloned embryo, but the purpose of the process (e.g. research, therapy or reproduction) is a separate matter.

There is also some misunderstanding regarding the difference between ‘therapeutic cloning’ and ‘reproductive cloning’. The firstmentioned is aimed at using the ES cells derived from SCNT in experiments focused on understanding disease and developing treatments for disease and not at creating a living (cloned) baby, as would be the goal of the latter. To date, no conclusive evidence exists that a human being has ever been cloned successfully, despite numerous claims in this regard over the past decade.[22]

Oocyte donation Carrying out SCNT requires oocytes, which have to come from female egg donors. Donating oocytes through hyper-ovulation is an invasive, time-consuming and painful process. Altruistic oocyte donation is therefore less common than sperm donation. For this reason, and to counter the demand for oocytes, it has been suggested that women

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donating oocytes receive, in addition to the conventional ‘out-ofpocket expenses’, fair compensation for physical discomfort, subject to strict ethical guidelines.[23] The South Korean Woo Suk Hwang scandal in 2006 best illustrates some of the more serious ethical risks associated with oocyte donation, namely inappropriate payment to oocyte donors (laboratory staff ), undue influence on these female employees to donate oocytes, as well as a high incidence of medical complications following the oocyte donation.[24] Fetal tissue that becomes available after abortion is another source of pluripotent stem cells. Apart from the moral issues relating to the source of these cells, i.e. abortion, the donation of this type of tissue is generally only permitted after the decision to terminate a pregnancy has been made.[19]

Induced pluripotent stem cells Induced pluripotent stem cells refer to somatic cells that can be reprogrammed to form pluripotent cells. As the reprogramming of these cells does not involve human embryos or oocytes, iPSCs are generally regarded as ethically unproblematic, as the concerns outlined above are absent. Obtaining the somatic cells (e.g. through a skin biopsy) is considered to be non-invasive when compared to the donation of oocytes used in the SCNT procedure. Concerns related to the use of iPSCs include possible downstream uses of the iPSC derivates, which may include the genetic modification of cells, large scale genomic sequencing, the sharing of cell lines among researchers, the possibility of deriving gametes in vitro from iPSCs and the commercialisation of applications involving the cells.[19] Recent studies have demonstrated the potential of iPSCs to differentiate into both male and female germ cells in different species. One of these includes the development of functional gametes and offspring in mice.[25] This example raises complex legal and ethical issues relating to the sequence and process of reproduction and genetic parentage, not to mention informed consent issues, concerns regarding cloning, as well as the potential to create an embryo by donors that may be unaware of such a possibility or attempt.

Intellectual property issues The question of intellectual property rights in the context of stem cell research is also fraught with ethical controversy, specifically concerning the patenting of living things or products of nature. In contrast to purified or isolated stem cells that are generally patentable as research tools, including the methods and reagents to grow and generate stem cell lines, there has been variance in legal approaches regarding the patenting of hESCs themselves (as living things) across jurisdictions, notably between Europe, the USA and Japan.[26] In 2008, the Expanded Appeal Board of the European Patent Office ruled that hESC lines for industrial or commercial purposes are not eligible for patent protection in Europe.[27] This ruling (in sharp contrast to the position in the USA) was followed by a ruling of the European Court of Justice in 2011 that banned patents on procedures involving the destruction of human embryos at any stage, including procedures used for the creation of hESC lines, as well as those using previously derived cell lines.[28] Intellectual property issues touch on a legal conundrum regarding the right of donors to retain property or proprietary interests in their own tissues, embryos or genetic material. The most commonly accepted view rejects property claims of research participants to

LEGISLATION biological material that they donated to research, despite the fact that their samples may lead to very profitable cell-line applications in which they will not share.[29] This may appear inequitable and conflicting if one considers the continuing rights of donors regarding the uses and secondary uses involving their tissue samples. On the other hand, property rights in embryos were (implicitly or explicitly) recognised by courts in the USA,[30] and also in respect of stored gametes (the USA,[31] Australia[32] and the UK[33]).

Informed consent and other issues More general ethical concerns relevant to the field of stem cell research and therapy are those relating to informed consent, specifically considering that cell lines may potentially be used indefinitely for future research not yet conceived. Questions arise as to the circumstances under which currently stored samples may be used for further stem cell research without consent, as well as the right of donors to withdraw their participation at any time during the research. Guideline documents on this issue differ, with some suggesting that donors can withdraw consent until the creation of an anonymised cell line,[34] and others until an embryo or blastocyst is used in the derivation of a cell line.[35] If donors may withdraw consent to participate in research once a cell line is created, this may drastically impact on further research. There is generally strong support for the right of withdrawal to endure.[36] Induced pluripotent stem cell research raises unique consent challenges that may require a specialised approach to consent (e.g. one that details common uses and possible uses of cell lines that donors may find problematical, for example producing human-animal chimeras and the derivation of human gametes).[37] Protecting the privacy and confidentiality of donors of tissues, gametes or embryos in the context of stem cell research always remains a concern, specifically as far as the potential traceability of stem cell lines is concerned.[37] The issue of how to address incidental findings (i.e. that a donor suffers or is likely to suffer from a specific disease) is another concern.

Stem cell research: Regulatory approaches With the permissibility and prohibition of specific activities as the yardstick for comparison, this section provides a broad global overview of distinctive legislative and policy approaches relating to stem cell research (Table 1). As noted earlier, these approaches reflect intricate and nuanced differences, which should be interpreted within the wider context of each jurisdiction’s legal, socio-economic, political and cultural tradition. In addition, the design of each regulatory framework may be influenced by specific or general statutory provisions or professional guidelines (as in India, for example) or by a combination of both.[16] All the jurisdictions listed below prohibit the reproductive cloning of human beings. The specific research activities involving embryos selected for comparison below are likewise not consistently and similarly articulated in the different legal and policy documents across these jurisdictions, with the result that in some instances, the permissibility or prohibition of these activities was deduced from more general proscriptions.

For example, a prohibition on the creation of human embryos for research or therapeutic purposes would include a prohibition of the use of SCNT to create an embryo.

Issues, on which policy variances across these jurisdictions are most evident, are the moral (and legal) status of the human embryo, the patenting of human tissues and payment of tissue and gamete donors. On the other hand, consensus is more uniform on the issues of prohibition of reproductive cloning, research standards, clinical readiness, cell line quality and scientific integrity.[2] Matters related to stem cell therapy (as opposed to research) will be considered separately, since this is a separate debate with an additional set of parameters.

Liberal At the one end of the spectrum are jurisdictions that permit a number of activities with regard to stem cell research, which include the creation and use of embryos and derivation of stem cell lines from various sources for a number of purposes. Liberal approaches, through tight regulations, generally permit SCNT under specific circumstances and are subject to procedural rules and governance mechanisms.

The overall objective of the liberal frameworks is to advance scientific progress, while at the same time taking into account public concerns.

Jurisdictions belonging to this category are, for example, Australia, Belgium, India, Iran, Israel, Japan, Singapore, South Korea, South Africa, Spain, Sweden, Taiwan, the UK and selected states in the USA (e.g. California, Illinois, Iowa, Maryland and New Jersey).

Moderate Jurisdictions adopting a moderate approach to stem cell research allow a measure of flexibility and typically permit a range of activities, subject to specific regulatory checks and balances. Jurisdictions belonging to this category attempt to strike a regulatory compromise between contradicting or diverse interests. Some of these jurisdictions permit research using surplus IVF embryos under specific circumstances, but may prohibit hESC derivation from other sources or involving specific techniques, such as embryos created using SCNT. The use of excess or surplus embryos is generally subject to conditions relating to informed consent of the donors, payment of donors and restrictions on the use of embryos beyond 14 days.

Countries whose stem cell regulatory frameworks may be considered moderate are, for example, Brazil, Canada, Denmark, Finland, France, Greece, the Netherlands, New Zealand, Norway, Slovenia, Switzerland, and some states in the USA (e.g. Arkansas, Montana, and Virginia).

Prohibitive Jurisdictions characterised as having adopted a restrictive approach expressly prohibit the creation and use of embryos for research purposes or for the derivation of hESCs, or may allow the use of imported hESC lines under tightly controlled and limited conditions.

Although some of these countries do not explicitly prohibit or ban therapeutic cloning, the creation of embryos for research purposes is prohibited, which implies curtailment of therapeutic cloning. The protection of human life and dignity in the contexts of eugenics and abortion is a specific legal concern in some of these jurisdictions (e.g.

Germany and Ireland).

Countries that fall into this category are Austria, Costa Rica, Germany, Ireland, Italy, Lithuania and some states in the USA (e.g.

Oklahoma).

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Table 1. Stem cell research: Regulatory approaches Jurisdiction *Legal position unclear, e.g. whether permitted or prohibited **No specific legislation regarding hESC research

Permit creation of human embryos for research, including SCNT

Prohibit creation of human embryos, including SCNT

Permit derivation of hESC lines from excess IVF embryos

√

Australia

√ √

Austria

√

√

Belgium

√ √

Brazil

√ √

Canada √

China

√ √

Costa Rica

√

√

√

*

√

France

√

√

Germany

√

Denmark *

Finland

√

√

Greece India

√

Iran

√

√ √

√

√

√

Israel

√ √

Italy

√

√

Japan

√

√ √

Lithuania

√

√

Mexico

√

√

Ireland

√

Netherlands

√

√

New Zealand

√

√

Norway

√

√

√**

Portugal √

Singapore

√

Slovakia

√**

Slovenia

√

√

South Africa

√

√

South Korea

√

√

Spain

√

√

Sweden

√

√

Switzerland

√

Taiwan UK USA (variation of laws within states)

Prohibit derivation of hESCs

Prohibit derivation of hESCs, but permit importation of hESC lines

√

√

√

√

√

No federal ban on hESC research, but restrictions on federal funding before 9 March 2009; federal funding only permitted for non-hESC research or those using hESC lines in existence prior to 9 August 2001. President Obama’s Executive Order lifted these restrictions for research involving new hESC lines. No federal funding under 2009 NIH Guidelines for research that creates human embryo for research purposes or destroys a human embryo (human cloning). √

Arkansas California

√

√

Connecticut

√

√ continued ...

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LEGISLATION

Table 1. (continued) Stem cell research: Regulatory approaches Jurisdiction *Legal position unclear, e.g. whether permitted or prohibited **No specific legislation regarding hESC research

Permit creation of human embryos for research, including SCNT

Prohibit creation of human embryos, including SCNT

Permit derivation of hESC lines from excess IVF embryos

Illinois

√

√

Iowa

√

√

Maryland

√

√

Massachusetts

√

Prohibit derivation of hESCs, but permit importation of hESC lines

√ √

Michigan

Prohibit derivation of hESCs

√

Montana

√

√

New Jersey

√

√

Oklahoma

√

Virginia

√*

√ √

A full list of legal references for the relevant laws and policies for each of the countries listed in this table can be obtained from the corresponding author (slabbmn@unisa.ac.za)

Stem cell therapy: Regulatory approaches Introduction The global regulation of stem cell therapies, similar to that of stem cell research, is characterised by legal uncertainty, with many jurisdictions revisiting regulatory systems to address the needs and challenges posed as cell and tissue therapies emerge. Effective global regulation is hampered by the diverse nature of stem cell-based products and that regulatory regimens differ with regard to the intended clinical use of the cell product, method of clinical delivery and manufacture.[38] The expansion of the harvested cells in vitro to generate a sufficient dose for therapeutic use, regarded as a more-than-minimally manipulated process, has added additional regulatory complexities, and products generated in this way are classified either as advanced therapy medicinal products (ATMPs) (the position in the EU) or biologics (the position in the USA).[9] Regulatory differences between the EU and the USA, for example, relate not only to the clinical trial requirements (e.g. the EU’s Clinical Trial Authorisation (CTA) and the Investigational New Drug application (IND) in the USA), but also to the data required to establish quality, safety and efficacy of cell therapies. Existing regulatory frameworks for the donation, procurement, processing and preservation of cells and tissues are often based on the so-called ‘conventional pharmaceutical paradigm’, which, considering the distinct features of stem cells, introduces obstacles with respect to the safety and efficacy of stem cell lines which are very different from other pharmaceutical products.[39] In addition, novel applications using hESCs or iPSCs may carry specific and unforeseen risks.

We will focus on the regulatory regimens for stem cell-based products in the EU and the USA, as this comparison will best illustrate the regulatory challenges associated with stem cell-based applications.

As this section will show, there is a need for greater harmonisation of regulatory standards and requirements across the world. One example is cell-device combinations, regulated as ATMPs in the EU but as medical devices in the USA, hence requiring different data from clinical trials in each of these instances. Current efforts to harmonise regulatory requirements include the International Conference on

Harmonisation (ICH),[40] and a European Medicines Agency-Food and Drug Administration (EMA-FDA) joint committee. Other instructive non-binding codes of practice or guidelines, referred to above, are those published by international bodies, such as the ISSCR and the Hinxton Group.

European Union Medicinal products based on human cells and tissues are classified (Table 2) as ATMPs in the EU (under Regulation (EC) 1394/2007) and can only be authorised for general use by the European Medicines Agency (EMA). The ATMP regulation enabled the European Commission to adopt specific requirements regarding issues such as good clinical practice, good manufacturing practices, the content of marketing authorisation applications, and the traceability of ATMPs.[41] ATMPs include gene therapy medicinal products, somatic cell products and tissue-engineered products. Provision is also made for the establishment of a Committee on Advanced Therapies (CAT), which provides a central cell therapy product evaluation procedure and assesses the quality, safety and efficacy of ATMPs for the final approval by the Committee for the Medicinal Products for Human Use (CHMP). Exempted from the ATMP regulations are products prepared on a ‘non-routine’ basis and used within the same member state in a hospital as prescribed for an individual patient.[42] This ‘hospital exemption’ allows patients to receive an ATMP under strictly controlled conditions in circumstances where there is no authorised medicinal product available. The interpretation of the so-called ‘hospital exemption’ is causing confusion in member states and will be discussed below.

Not all of the manufacturing processes for ATMPs fall under the ATMP regulations when the ATMPs are produced from human tissues or cells. The 2004 European Union Human Tissues and Cells Directive (EUTCD)[43] provides quality and safety standards for human tissues and cells used for therapeutic purposes, and applies to all stages from donation to processing, storage and distribution. Implemented at a national level, it sets out the requirements for the accreditation, designation, authorisation, or licensing for the procurement and testing of the biological material intended for human applications.

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LEGISLATION Products containing human tissues or cells (viable or non-viable) cannot be classified as medical devices in the EU in terms of the Council Directive concerning medical devices,[44] despite containing elements of medical devices, unlike the position in the USA (see discussion below).

United States of America (Table 3) The US Food and Drug Administration (FDA) is the regulatory authority responsible for the regulation of, among others, therapeutic products, which may include drugs, devices, biological or combination products (containing two or more different regulated components, e.g. drug and device or biologic and device). Regulations in the Code of Federal Regulations (CFR) pertaining to cell therapy products are the Investigational New Drugs (IND) regulations (21 CFR 312), biologics regulations (21 CFR 600), regulations on human cells, tissues and cellular and tissue-based products (HCT/P)s (regulations; 21 CFR 1271), and current good manufacturing practice regulations (21 CFR 211). The FDA’s HCT/P regulations create a tiered framework based on sections 351 and 361 of the Public Health Services Act (PHSA). HCT/ Ps, described as articles ‘containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion or transfer into a person’ (21 CFR 1271.3(d)), are subject to the HCT/ Ps regulations, unless removed from a patient and implanted into the same patient as part of the same surgical procedure (21 CFR 1271.15(b)).[45] Although subject to the HCT/Ps regulations, no licence is necessary for section 361 HTC/Ps that meet certain criteria, e.g. if minimally manipulated, intended for homologous use and not combined with any other product, and autologous, e.g. the patient is treated with his or her own cells (21 CFR 1271.10(a)). HCT/Ps not meeting these criteria, however, are also subject to the good tissue practice requirements[46] and will in addition be regulated as drugs, biologics or devices under section 351 of the PHSA (21 CFR 1271.20). Stem cellbased therapies involving more than minimally manipulated cells will mostly fall within the last-mentioned category, even if used for autologous purposes.

The meaning of ‘more than minimally manipulated’ was highlighted in the USA in a 2014 judgment. This case revolved around the FDA’s action against Regenerative Sciences, LLC, who manufactured a product called Regenexx™, consisting of autologous mesenchymal stem cells manipulated outside of the body and injected back into patients with orthopaedic injuries. The US Circuit Court of Appeals for the District of Columbia held that: (i) the cell mixture used for this procedure contained both a drug and biologic; (ii) it was more than minimally manipulated under section 351 of the PHSA; (iii) it qualified as interstate commerce; and (iv) was hence subject to the regulation and approval of the FDA.[47] In terms of the FDA framework, physicians may administer more than minimally manipulated stem cell products to patients in two ways. The first is permitted in accordance with the FDA’s programme for ‘expanded access to investigational drugs and biological products for treatment use’, better known as ‘compassionate use’, provided that the product in question is being tested in a present clinical trial and only if expanded access will not interfere with the conduct of clinical investigations.[48] Clinicians are allowed to charge patients to recover direct costs, as well as those administrative costs associated with expanded access use. The second exception is the ‘off-label

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prescribing’ of FDA-approved stem cell products, which refers to the prescribing of medicine in a manner that differs from the specified instructions.[49] It is generally accepted in both the EU and USA that the deliberate expansion of cells in culture substitutes more than minimal manipulation. Manipulated autologous cells for structural use, on the other hand, fall within the ambit of somatic cell therapy products and require an ‘investigational new drug’ (IND) exemption or the FDA license approval.

The FDA facilitates regulatory compliance through guidance documents via the Centre for Biologics Evaluation and Research (CBER).

The FDA offers advisory committee meetings which may discuss pertinent questions relating to a particular product or product area. The Office of Cellular, Tissue and Gene Therapies’ (OCTGT) own committee, the Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC), is tasked to discuss cell-therapy products. Various guidance documents provide clarity on specific regulatory issues. For example, HCT/Ps from adipose tissue[50] and minimally manipulated HCT/Ps[51] are the focus of recent FDA draft guidance documents.

Regulatory challenges There is no doubt that stem cell-based therapies are developing very fast and that regulatory frameworks should be flexible enough to accommodate the pace of scientific progress. It is generally agreed that more research is necessary on the procedures to establish the safety and efficacy of stem cell products and the prediction of potential risks. Most regulatory models seem to follow a risk-based approach that focuses on both extrinsic issues (e.g. donor selection, sample procurement to limit risk of transmitting communicable diseases, and manufacturing and handling practices) and intrinsic issues (such as cell origin). Safety issues (following reports of serious adverse events) seem to receive more attention than efficacy issues.

This makes the conventional pharmaceutical regulatory model an uncomfortable fit for the clinical translation of the cells into products.

There is a need for the global harmonisation of guidelines covering a broad range of issues, which due to the limited scope of this article, cannot be discussed. Despite broadly similar regulatory requirements and procedures with regard to product pre-market approval processes (to establish safety, efficacy and quality), regulation of clinical trials using Good Clinical Practice (GCP) and regulation and licensing of manufacturing using Good Manufacturing Practice (GMP) (primarily the result of increased harmonisation of therapeutic product regulation under the auspices of the ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use), specific disparities remain. Two examples are the issues of donor eligibility and the suitability of stem cell lines for use in clinical trials and subsequent commercialisation.[52] The legal regulation of human tissue (governing the procurement, use and disposal of human tissue) and tissue establishments across jurisdictions is also diverse, creating additional obstacles.

Harmonisation attempts are furthermore hampered by ambiguity and uncertainty with regard to the following issues: Product classification The scope of what constitutes cell-based products is unclear. The term ‘stem cell-based products’ refers to ‘products intended to be administered to a patient’, which ‘contain or are derived from stem

LEGISLATION

Table 2. EU regulatory framework (selected documents) EU

EMA CHMP CAT

Regulation/directive Regulation (EC) No. 1394/2007

Of the European Parliament and of the Council on ATMPs

Regulation (EU) No. 536/2014

Of the European Parliament and of the Council on clinical trials on medicinal products for human use, repealing Directive 2001/20/EC

Directive 2004/23/EC

EUTCD, which establishes the standard quality, donation safety, harvesting, tests, processing, preservation, storage, and distribution of human tissues and cells

Directive 2006/17/EC

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

Directive 2003/94/EC

Good manufacturing practice for medicinal products for human use and investigational medicinal products for human use

Directive 2001/83/EC Directive 2009/120/EC

Medicinal products for human use (includes 2003/63/EC, 2004/27/EC and advanced therapy regulation).

Commission Directive 2009/120/EC amending Directive 2001/83/EC of the European Parliament and of the Council on the community code relating to medicinal products for human use as regards ATMPs.

Table 3. USA regulatory framework (selected documents) USA

FDA CBER OCTG) CTGTAC

Regulation

Legislation: Public Health Service Act, sections 351 and 361 [42 USC 264] Regulations for Investigational New Drugs (IND), Code of Federal Regulations, Part 312

21 CFR 1271*

Human Cells, tissue, cellular- and tissue-based products

21 CFR 210

Current good manufacturing practice in manufacturing, processing, packaging or holding of drugs

21 CFR 211

Current good manufacturing practice for finished pharmaceuticals

21 CFR 600 21 CFR 610

Description of general safety and sterility tests administered by parenteral routes (note, this is not a safety test of the product itself ).

21 CFR 314 21 CFF 312

Adequate and well-controlled clinical trials

21 CFR 50 21 CFR 56

Subpart B. Informed consent of human subjects

21 CFR 58

Good laboratory practices for nonclinical laboratory studies

*For tissues and cells procured after 25 May 2005

cells’.[53] These include three therapeutic concepts for the use of stem cells, namely direct administration, transplantation of differentiated stem cell progeny, and tissue

engineering.[53] As far as direct administration is concerned, stem cells are introduced either locally or systemically into a patient’s body, after which the cells migrate to the intended site

where differentiation into the appropriate cell type takes place.[53] With transplantation, the stem cells are first cultivated in vitro, followed by their differentiation into the desired tissue type, before being transplanted into the patient. In the case of tissue engineering, cells are seeded or implanted onto a scaffold or matrix, where the combination approximates the desired tissue.[53] Adding to the complexity is the fact that in any of these applications, cells from different sources may be used (as discussed earlier in this article), resulting in the eventual product being classified as either allogeneic (cells from a donor are used), autologous (recipient’s own cells are used), or xenogeneic (cells from another species are used).[53] The unique nature of these products means that methods and standards traditionally used with regard to conventional pharmaceutical products to ensure the safety, efficacy and quality of the stem cell-based products, may not be sufficient. Combination products are also addressed very differently across jurisdictions. Although products falling within two or more categories are normally assessed according to their principal or primary mode of action (PMOA), assessed on a case-by-case basis, this assessment cannot always be made with certainty and may lead to undesired results.[53] Product categories within the EU and the USA have their own challenges. In the EU, for example, ATMPs include three types of medicinal products, namely gene therapies, somatic cell therapies, and tissue engineered products. It is often difficult to determine to which of these categories a product belongs. Another controversial assessment is the question of whether manipulation of a living material is minimal or substantial.

Moreover, some of the new biological products could easily fit one or more of the categories of medicines, medical devices, cosmetics, or tissues and cells. Regulatory discrepancies in this regard may mean that one product may be subject to different requirements across the EU. These disparities will negatively impact on incentives to develop ATMPs by discouraging investments, distorting competition between developers and impeding the free movement of these products.[54] ‘Minimally manipulated v. ‘substantially manipulated’ The interpretation of ‘minimally manipulated’ stem cells is important for various reasons.

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LEGISLATION Most significantly, if the stem cells were more than minimally manipulated, the product is legally destined for the more stringent and expensive ‘drug pathway’ for broad clinical use, which includes, for example, the controlling of the resulting products through mandated premarket testing for safety and efficacy in specified indications and the conducting of a series of registered multiphase (I-III) clinical trials.

The Regenexx™ case, referred to above, prompted the publication of guidelines by the FDA in December 2014 on minimally manipulated cells.[55] For example, manipulations with adipose tissue (e.g. isolating cells from adipose tissue) will in future be considered to be more than minimally manipulated, as this changes the original characteristics of the cells.[55] These guidelines will be instructive for other jurisdictions where the regulatory framework for stem cell-based therapies is immature or silent on a range of issues relating to the regulation of cell based therapies.

his daughter was entitled to receive a controversial stem cell treatment offered by the Stamina Foundation. Dismissing Mr Durisotto’s claim, the court stated that the Italian ruling rightly pursued the legitimate aim of protecting health and that the ruling was proportionate to this aim. Despite the emphasis on demonstrated efficacy, the court did not distinguish between compassionate treatments and unproven therapies, except to confirm that unproven therapies may not be used for compassionate purposes.

The increase in unsafe individualised treatments or experimental treatments offered to patients outside of the scope of a medicines regulatory framework demonstrates that, once again, clarity is required, as the laws and regulations governing medical practice and the conduct of healthcare professionals may not always be sufficient to address these issues.

Treatments or products exempted from product regulation The legal regulation of stem cell treatments, which are exempted from product regulation, is likewise inconsistent across jurisdictions. Products assessed as having minimal risks and not posing serious safety concerns are normally subject to limited regulatory oversight. Autologous cells that: (i) have not been manipulated extensively or combined with other articles; (ii) are intended for homologous use in functionally compatible tissues, and/or (iii) are harvested and transplanted as part of the same surgical procedure, are generally exempted from product regulation, such as hematopoietic stem cell transplants aimed at restoring bone marrow function.[56] In this regard, different interpretations exist regarding the level of manipulation (e.g. the exact meaning of ‘minimally’ or ‘more than minimally manipulated’) and the intended use of the cells across jurisdictions, as well as definitions used to describe these processes. Concepts such as ‘homologous’ or ‘non-substantial’ are likewise not always clearly defined, leading to diverse assessments of which cells are classified as posing a ‘minimal risk’ and those requiring more stringent regulation.[56] This uncertainty also extends to more than minimally manipulated cell-based products, regulated as drugs in exceptional instances where patients are provided with access to medicinal products lacking the relevant evidence required for market licensing. These exemptions are regulated differently across jurisdictions and under different descriptions, such as ‘compassionate use’ or ‘special access’ provisions (e.g. in the USA). These exceptions fall within the scope of the regulation of medical practice, often with additional oversight mechanisms, such as approval from an institutional review board, or as is the case in the EU, under the so-called ‘hospital exemption’, referred to above. The scope of the ‘hospital exemption’ is also not clearly and uniformly understood in the different member states and related terms, such as ‘prepared on a non-routine basis’, referred to in the discussion on the EU above, are equally obscure.[57] The legal uncertainty in this context is underscored by a 2014 decision of the European Court of Human Rights in Durisotto v. Italy.[58] This case concerns a patient’s appeal to a ruling of an Italian court that denied the patient access to an unproven stem cell treatment, based on an alleged infringement of several articles of the European Convention of Human Rights. The judgment made it clear that patients do not have an automatic right (on compassionate grounds) to a stem cell treatment that lacks evidence of efficacy. Mr Nivio Durisotto, whose daughter (the patient) suffers from a degenerative brain disease, insisted that

This paper is premised on the assumption that a comparative understanding of the global regulatory framework with regard to stem cell research and therapy will assist in formulating more effective, better harmonised and ethical legal responses to a very complex and rapidly evolving scientific field. The paper first considered a few issues that raise specific ethical concerns, which include, among others, moral perceptions regarding the human embryo, reproductive and therapeutic cloning, oocyte donation, intellectual property rights in tissues and cells and issues relating to privacy, confidentiality and informed consent.

A comparative overview focusing on 35 selected jurisdictions was undertaken next, using as a yardstick for comparison the permissibility or prohibition of specific stem cell research activities in these countries including the creation of human embryos through processes such as IVF and SCNT and the resulting derivation of hESC lines. A distinction was drawn between so-called liberal and permissive regulatory regimens (e.g. those that permit embryo research and the derivation of hECS from various sources and technologies, such as IVF and SCNT); moderate regimens that follow a regulatory compromise (e.g. those that may permit research using excess IVF embryos, but prohibit hESC derivation from other sources); and finally, those restrictive jurisdictions that prohibit embryo research and related activities (e.g. the use of excess IVF embryos in hESC research and the derivation of hESC lines). This comparative overview illustrates that issues on which legal and policy variance is the most divergent are the moral and legal status of the human embryo and the patenting of human tissues, whereas consensus appears more evident with regard to the prohibition of reproductive cloning. In addition, it emerges that the transnational sharing of stem cell lines and data across jurisdictions will depend on the success with which jurisdictions succeed in harmonising laws and policies in key areas, most notably those relating to research oversight, technical standards, quality assurance and operating procedures.

The discussion on the legal regulation of stem cell-based products reveals very specific and unique challenges that make the traditional pharmaceutical regulatory model a poor fit for the clinical translation of stem cells. Firstly, issues revolving around product classification need to be clarified, as novel stem cell products may exhibit complex characteristics that could belong to more than one of the existing product classifications (e.g. medicines and medical devices). Clear, flexible and predictable guidelines and definitions are necessary to

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August 2015, Vol. 8, No. 2, Supplement 1 SAJBL

Conclusion

LEGISLATION deal with these overlapping, combination or borderline products, considering the likelihood the new product types may defy existing product classifications. Secondly, the position with regard to the regulation of novel and individualised stem cell products or treatments should also be more transparent, particularly in view of the proliferation of unsafe or potentially harmful experimental treatments offered to vulnerable patients, which generally fall outside of the scope of the regulation of medicines. The recent judgment of the European Court of Human Rights concerning a patient’s claim to have access to an unproven experimental stem cell treatment demonstrates how unsettled the current legal regulatory framework relating to stem cell therapies is, not to mention the need to strike a balance between patient expectations and entitlements with regard to unproven treatments and the broader objective of the protection of vulnerable patients from unsafe and potentially harmful treatments. The regulation of these exemptions should not be exploited, particularly if there is no reasonable justification for subjecting the patient to serious unforeseen risks. Thirdly, different understandings of key concepts in the regulatory context, such as ‘minimally manipulated’ cells or cells ‘prepared on a non-routine basis’ provide another obstacle.

The swiftly evolving field of stem cell research and therapy will continue to place high demands on regulators and policymakers to provide clear and unambiguous, yet flexible rules and guidelines.

A balance will need to be achieved between governing stem cell research and not impeding its clinical translation. There is no doubt that collaborative efforts, some of which are referred to in this paper, will yield the most promising results in providing harmonised solutions to some of the legal lacunae and ambiguities referred to herein.

Considered a permissive legal system as far as stem cell research is concerned, South Africa specifically needs to take cognisance of the lessons and shared best practices emanating from the global domain.

Funding. This research and the publication thereof is the result of funding provided by the Medical Research Council of South Africa in terms of the MRC’s Flagships Awards Project SAMRC-RFA-UFSP-01-2013/ STEM CELL.

References 1. Isasi RM. Policy interoperability in stem cell research: Demystifying harmonization.

Stem Cell Rev 2009;5(2):108-115. [http://dx.doi.org/10.1007/s12015-009-9067-z] 2. Caulfield T, Zarzeczny A, McCormick J, et al. The stem cell research environment: A patchwork of patchworks. Stem Cell Rev 2009;5(2):82-88. [http://dx.doi. org/10.1007/s12015-009-9071-3] 3. Caulfield T, Zarzeczny A, McCormick J, et al. International stem cell environments: A world of difference. Nature Reports Stem Cells 2009;4. [http://dx.doi.org/10.1038/ stemcells.2009.61] 4. Cohen CB. Renewing the Stuff of Life: Stem Cells, Ethics, and Public Policy. Oxford: Oxford University Press, 2007:140.

5. Isasi RM, Knoppers, B. Beyond the permissibility of embryonic and stem cell research: Substantive requirements and procedural safeguards. Hum Reprod 2006; 21(1):2747-2481. [http://dx.doi.org/10.1093/humrep/del235] 6. Trounson C, Baum E, Gibbons, D, et al. Developing a case study model for successful translation of stem cell therapies. Cell Stem Cell 2010;6(6):513-516. [http://dx.doi.org/10.1016/j.stem.2010.05.008] 7. Kiatpongsan S, Sipp D. Monitoring and regulating offshore stem cell clinics.

Science 2009;323:1564-1565. [http://dx.doi.org/10.1126/science.1168451].

8. Lomax G, McNab A. Harmonizing standards and coding for hESC research. Cell Stem Cell 2008;2(3):201-203. [http://dx.doi.org/10.1016/j.stem.2008.02.002] 9. Pardo R, Calvo F. Attitudes toward embryo research, worldviews, the moral status of the embryo frame. Science Communication 2008;30(1):8-47. [http://dx.doi. org/10.1177/1075547008319432] 10. Slabbert M. Cloning and stem cell research: A critical overview of the present legislative regime in Australia and the way forward. J Law Med 2003;10(4):514-530.

11. Slabbert M. The fetus and embryo: Legal status and personhood. Tydskrif vir die Suid-Afrikaanse Reg (Journal of South African Law) 1997;2:234-255.

12. Republic of South Africa. National Health Act 61, Section 1. Pretoria: Government Gazette 2003.

13. Australia. Section 1, Research Involving Human Embryos Act No 145 of 2002 (Cth).

14. Indian Council of Medical Research. Guidelines for Stem Cell Research (2012).

India: Indian Council of Medical Research, 2012. http://icmr.nic.in/stem_cell/ stem_cell_guidelines.pdf (accessed 2 January 2015).

15. Republic of South Africa. Human Cloning and Other Prohibited Practices Act. Government Gazette 2 September 2004.

16. Isasi MR, Knoppers BM. Mind the gap: Policy approaches to stem cell and cloning research in 50 countries. Eur J of Health Law 2006;13(1):9-26. [http://dx.doi. org/10.1163/157180906777036328] 17. European Union. Judgment of the Court of Justice of the European Union, Grand Chamber. Case 6-364/13 (18 December 2014). http://curia.europa.eu/juris/ document/document.jsf?text=&docid=160936&pageIndex=0&doclang=EN&m ode=req&dir=&occ=first&part=1&cid=61843 (accessed 24 January 2015).

18. International Stem Cell Corporation v. Comptroller General of Patents, Designs and Trade Marks [2013] EWHC 807. http://www.bailii.org/ew/cases/EWHC/ Ch/2013/807.html (accessed 24 January 2015).

19. Lo B, Parham L. Ethical issues in stem cell research. Endocr Rev 2008;30(3):204-225. [http://dx.doi.org/10.1210/er.2008-0031].

20. Tashibana M, Amato P, Sparman M, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 2013;153(6):1228-1238. [http://dx.doi. org/10.1016/j.cell.2013.05.006].

21. United Nations. Declaration on Human Cloning. GA Res., UNGAOR, 59th Sess., UN Doc. A/280 (2005). http://www.un.org/press/en/2005/ga10333.doc.htm (accessed 27 July 2015).

22. Schlesinger F. I have cloned a human: Extraordinary claims of a doctor who ‘has implanted embryos into four women’. Mail Online; 22 April 2009. http://www. dailymail.co.uk/sciencetech/article-1172487/Ive-cloned-human-Astonishingclaims-doctor-implanted-embryos-women.html (accessed 3 January 2015).

23. Hyun I. Moving human SCNT research forward ethically. Cell Stem Cell 2011;9(4):295-297. [http://dx.doi.org/10.1016/j.stem.2011.08.001] 24. Van der Heyden MAG, van de Ven T, Opthof T. Fraud and misconduct in science: The stem cell seduction. Netherlands Heart Journal 2009;17(1):25-29. [http:// dx.doi.org/10.1007/BF03086211] 25. Botman O, Wyns C. Induced pluripotent stem cell potential in medicine, specifically focused on reproductive medicine. Front Surg 2014(1):1-10. [http:// dx.doi.org/10.3389/fsurg.2014/00005].

26. The Hinxton Group. Proprietary challenges in stem cell research. Baltimore; The Hinxton Group. https://hinxtongroup.wordpress.com/background-2/iplandscape/ (accessed 5 January 2015).

27. Expanded Appeal Board, European Patent Office (EPO). Case G0002/06 (Use of embryos/WARF) of 25 November 2008. http://www.epo.org/law-practice/ case-law-appeals/recent/g060002ex1.html (accessed 6 January 2015).

28. European Union. Court of Justice of the European Union (2011). Oliver Brüstle v.

Greenpeace eV. Judgment of the Court (Grand Chamber), 18 October 2011 (Case C-34/10). http://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:62010CJ0 034:EN:HTML (accessed 6 January 2015).

29. Moore v. Regents of the University of California 51 Cal. 3d. 120, 793 P.2d. 479, 271 Cal. Rptr. 146, CA. 1990.

30. Dahl v. Angle 222 Ore App 572 (Or Ct App, 2008).

31. Hecht v. Superior Court of Los Angeles County, 20 Cal Rptr 2d 275 (Cal Ct App, 1993).

32. Australia. Supreme Court of Western Australia. Ex parte C [2013] WASC 3 (2 January 2013).

33. Yearworth v. North Bristol NHS Trust [2009] 3 WLR 118.

34. Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada. Tri-Council Policy Statement. Ethical Guidelines for Research involving Humans. Ottowa: Government of Canada, 2014: Chapter 12. http://www. pre.ethics.gc.ca/pdf/eng/tcps2/TCPS_2_FINAL_Web.pdf (accessed 27 July 2015).

35. International Society for Stem Cell Research. Guidelines for the Conduct of Human Embryonic Stem Cell Research. ISSCR; 2006:par 11.2. http://www.isscr.org/home/ publications/guide-clintrans (accessed 27 July 2015).

36. Caulfied T, Ogbogu U, Isasi R. Informed consent in embryonic stem cell research: Are we following basic principles? CMAJ 2007;176(12):1722-1725. [http://dx.doi. org/10.1503/cmaj.061675] 37. Aalto-Setälä K, Conklin BR, Lo B. Obtaining consent for future research with induced pluripotent cells: Opportunities and challenges. PLos Biol 2009;7(2):e42. [http://dx.doi.org/10.1371/journal.pbio.1000042] 38. Hourd P, Chandra A, Medcalf N, et al. Regulatory challenges for the manufacture and scale-out of autologous cell therapies. In: The Stem Cell Research Community.

StemBook. June 30, 2014. http://www.stembook.org/node/5702 (accessed 4 January 2015). [http://dx.doi.org/10.3824/stembook.1.96.1].

39. Isasi R, Knoppers BM. From banking to international governance: Fostering innovation in stem cell research. Stem Cells Int 2011;498132:1-8 [http://dx.doi. org/10.4061/2011/498132].

August 2015, Vol. 8, No. 2, Supplement 1 SAJBL

21

LEGISLATION 40. International Conference on Harmonisation of Technical Standards for Registration of Pharmaceuticals. http://www.ich.org/home.html (accessed 2 February 2015).

41. European Parliament and Council of the European Union. ATMP Regulation (EC) 1394/2007, Part IV, Annex to Directive 2001/83/EC, adopted 14 September 2009 (as amended). http://ec.europa.eu/health/index_en.htm (accessed 27 July 2015).

42. European Parliament and Council of the European Union. ATMP Regulation, article 28(2), amending article 3 of Directive 2001/83. (2001). http://ec.europa.eu/ health/index_en.htm (accessed 27 July 2015).

43. European Parliament and Council of the European Union. Directive 2004/23/ EC. (2004). http://ec.europa.eu/health/blood_tissues_organs/key_documents/ index_en.htm (accessed 27 July 2015).

44. European Parliament and Council of the European Union. Directive 93/42/ EEC. (1993, article 1.5(f )). http://eur-lex.europa.eu/legal-content/EN/ NOT/?uri=CELEX:31993L0042 (accessed 27 July 2015).

45. US Food and Drug Administration. Draft Guidance for Industry - Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception. (2014). http://www.fda.gov/BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/Guidances/Tissue/ucm419911.htm (accessed 15 January 2015).

46. EUR-Lex. Access to European Union Law. http://eur-lex.europa.eu/legal-content/ EN/ALL/?uri=CELEX:32004L0023 (accessed 6 February 2015).

47. United States v. Regenerative Sciences, LLC, No 12-5254 F 3d (D.C. Cir. 2014).

48. US Food and Drug Administration. Draft guidance for industry - Individual patient expanded access: Form FDA 3926. (2015). https://www.federalregister.gov/ articles/2015/02/10/2015-02561/individual-patient-expanded-access-applicationsform-fda-3926-draft-guidance-for-industry 2015 (accessed 27 July 2015).

49. US Food and Drug Administration. Guidance document – ‘Off-label’ and investigational use of marketed drugs, biologics and medical devices 2014. http:// www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm (accessed 25 January 2015).

50. US Food and Drug Administration. Draft guidance - Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) from Adipose Tissue: Regulatory Considerations 2014. http://www.fda.gov/BiologicsBloodVaccines/

22

August 2015, Vol. 8, No. 2, Supplement 1 SAJBL

GuidanceComplianceRegulatoryInformation/Guidances/Tissue/ucm427795. htm#INTRO (accessed 25 January 2015).

51. US Food and Drug Administration. Draft guidance - Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products 2014. http://www. fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ Guidances/CellularandGeneTherapy/ucm427692.htm (accessed 25 January 2015).

52. Feigal EG, Tsokas G, Viswanathan S, et al. Proceedings: International regulatory consideration on development pathways for stem cell therapies. Stem Cells Transl Med 2014;3(8):879-887. [http://dx.doi.org/10.5966/sctm.2014-0122] 53. Von Tigerstrom B. The challenges of regulating stem cell based products.

Trends Biotechnol 2008;26(12):653-659. [http://dx.doic.org/ 10.1016/j. tibtech.2008.08.004] 54. European Union. Report from the EC to the European Parliament and the Council in accordance with Article 25 of Regulation (EC) No 1394/2007 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 (28 March 2014). http://ec.europa.eu/health/files/advtherapies/2014_atmp/atmp_en.pdf (accessed 6 February 2015).

55. US Food and Drug Administration. Draft guidance - Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products . (2014). http://www. fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ Guidances/CellularandGeneTherapy/ucm427692.htm (accessed 25 January 2015).

56. Lysagth T, Kerridge I, Sipp D, et al. Oversight for clinical uses of autologous adult stem cells: Lessons from international regulations. Cell Stem Cell 2013;13:647-651. [http://dx.doic.org/10.1016/j.stem.2013.11.013] 57. Cuende N, Boniface C, Bravery C, et al. The puzzling situation of hospital exemption for advanced therapy medicinal products in Europe and stakeholders’ concerns. Cytotherapy 2014;16(12):1597-1600. [http://dx.doi.org/10.1016/j. jcyt.2014.08.007] 58. European Court of Human Rights. Durisotto v. Italy. Application no 62804/13.

ECHR 153 (2014). http://hudoc.echr.coe.int/sites/eng-press/pages/search. aspx?i=003-4774464-5811888#{“itemid”:[“003-4774464-5811888”]} (accessed 6 February 2015).

PLURIPOTENT STEM CELLS

Legislation governing pluripotent stem cells in South Africa M S Pepper,1 MB ChB, PhD, MD; C Gouveia,2 BSc, BSc Hons;Â M NĹ‘thling Slabbert,3 BA, BA Hons, MA DLitt, LLB, LLD Department of Immunology, Institute for Cellular and Molecular Medicine, and MRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, South Africa; Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Switzerland 2 Department of Immunology, Institute for Cellular and Molecular Medicine, and MRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, South Africa 3 Department of Jurisprudence, School of Law, University of South Africa, Pretoria, South Africa 1

Corresponding author: M S Pepper (Michael.pepper@up.ac.za)

One of the most exciting areas of medical research involves the use of stem cells for the treatment of patients with a variety of diseases and for tissue repair. Although stem cell research is accelerating rapidly in many countries, it has in the past been limited in South Africa (SA); very little has been done in this country to explore the great potential offered by stem cells to address the high disease burden. Stem cell therapy has however been practised for many years, in SA and worldwide, in the form of haematopoietic stem cell transplantation, mainly for haematological malignancies.

From a therapeutic perspective, two types of stem cells can be defined: pluripotent stem cells and adult stem cells. Pluripotent cells derived from the inner cell mass of blastocysts (either from in vitro fertilisation or following somatic cell nuclear transfer) are called embryonic stem (ES) cells, while those derived by reprogramming adult cells are called induced pluripotent stem (iPS) cells. Adult stem cells include haematopoietic, mesenchymal and neural stem cells.

The purpose of this article is to critically examine the SA legislation with regard to elements that impact on pluripotent stem cell research and the use of pluripotent stem cells for therapeutic purposes. This includes (but is not limited to) legislation from the National Health Act (Chapter 8 in particular) and its regulations, and deals with matters related to research on embryos in the stem cell context, somatic cell nuclear transfer, reproductive and therapeutic cloning and the generation and therapeutic use of iPS and ES cells.

S Afr J BL. 2015;8(2 Suppl 1):23-31. DOI:10.7196/SAJBL.8402

In order to be defined as a stem cell, a cell must be able to divide to ensure self-renewal, and to differentiate (Fig. 1). The earliest stem cell from a developmental perspective is the fertilised egg (zygote) (Fig. 2).

populations of stem cells becomes restricted, and cells are said to be pluripotent, multipotent and finally unipotent. Progenitor cells have a limited number of cell divisions and may be multipotent or unipotent.

The zygote is totipotent, i.e. it is capable of giving rise to all of the extraembryonic and embryonic tissues of the developing embryo. As development progresses, the differentiation potential of successive

Fig. 2. From fertilisation to blastocyst formation. A zygote results from the fertilisation of an egg by a sperm. After three rounds of division, an 8-cell embryo can be recognised, and following compaction and morula formation this goes on to form a blastocyst. The blastocyst consists of an inner cell mass Fig. 1. Definition of a stem cell. In order to be defined as a stem cell, a cell must be able to divide and to differentiate. To ensure a continuing source of cells capable of self-renewal, at least one of the resulting daughter cells should remain a stem cell.

which goes on to develop into the embryo proper, while the outer layer, the trophoblast, goes on to form the placenta. Micrographs in the lower half of the figure were provided by Prof. Carin Huyser (Reproductive Biology Laboratory, Department of Obstetrics and Gynaecology, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa).

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PLURIPOTENT STEM CELLS The adult human is made up of approximately 4×1013 cells,[1] and there are more than 200 different cell types in the human body.

Approximately 200 million (2×108 ) cells are lost from the body of an adult per minute, and their replacement is assured by adult stem cells throughout life. Adult stem cells are found in most tissues including bone marrow, skin, skeletal muscle, intestinal mucosa, liver and neural tissue. With the exception of haematopoietic stem cells (HSCs), these cells are limited in number, are difficult to isolate and their therapeutic potential remains largely undefined. HSCs derived from the bone marrow, peripheral blood (following growth factor mobilisation of bone marrow cells) or neonatal blood (harvested immediately after birth via the umbilical cord from the placenta) have been used successfully and for several decades for haematopoietic stem cell transplantation (HSCT) for the treatment of neoplastic, haematological and genetic diseases.

Pluripotent stem cells, the topic of this article, are on the other hand more complex with regard to their derivation, and in some

cases are associated with important ethical considerations. Their therapeutic potential is only beginning to be explored. Table 1 highlights the salient differences between adult and pluripotent stem cells.

Pluripotent stem cells include embryonic stem cells (ES cells) and induced pluripotent stem cells (iPS cells). ES cells are derived from the inner cell mass (ICM) of the blastocyst.

Blastocysts are obtained either from IVF or following the process of somatic cell nuclear transfer (SCNT). The iPS cells are derived from adult cells which are induced to dedifferentiate following the introduction of genes which code for transcription factors involved in early embryonic development (Fig. 3). The derivation of pluripotent stem cells is summarised in Table 2.

ES and iPS cells can develop into almost every cell type in the body (hence their categorisation as pluripotent). ES and iPS cells have great potential value for understanding disease processes, for drug screening and potentially for therapeutic purposes, although the latter is only beginning to be

Table 1. Adult v. pluripotent stem cells Adult

Differentiation potential generally limited to cells of tissue in which they reside Readily available No ethical issues No evidence for tumorigenesis Therapeutic value well demonstrated

Pluripotent

HSCs for bone marrow transplantation MSCs: >500 registered clinical trials

Differentiation potential: all of the body’s cell types Technically more difficult to obtain Ethical issues related to ES cells Potential for tumorigenesis Therapeutic value – remains to be determined Value: understanding disease processes, drug screening

MSCs = mesenchymal stem cells

Table 2. Pluripotent stem cells

Name

Origin

Embryonic stem cell

Blastocyst

Induced pluripotent stem cell

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Legislation pertaining to embryos applicable Derived from IVF

Yes

Derived by SCNT (therapeutic cloning)

Yes

Somatic cell

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No

defined. However, ES cells, irrespective of the means through which they are derived, are the source of much controversy, since their isolation is interpreted by some as necessitating the destruction of life.

Finally, it should be noted that the 2012 Nobel Prize in physiology or medicine was awarded jointly to John B Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent.[2]

Removal and/or withdrawal and use of human tissue, blood, blood products and gametes Section 56 of Chapter 8 of the National Health Act (NHA)[3] entitled ‘Use of tissue, blood, blood products or gametes removed or withdrawn from living persons’, stipulates in subsection (1) that ‘[a] person may use tissue or gametes removed or blood or a blood product withdrawn from a living person only for such medical or dental purposes as may be prescribed’. The interpretation of ‘prescribed’ is understood to mean established medical practice. Where this is not the case, it is understood that any other ‘purposes’ would first need to be validated in the context of a clinical trial.[4] Subsection (2) stipulates that ministerial authorisation is needed for removal or withdrawal of tissue, blood, blood products or gametes from a living person under the following conditions: ‘(i) Tissue, blood, a blood product or a gamete from a person who is mentally ill within the meaning of the Mental Health Care Act, 2002 (Act No. 17 of 2002); (ii) tissue which is not replaceable by natural processes from a person younger than 18 years; (iii) a gamete from a person younger than 18 years; or (iv) placenta, embryonic or foetal tissue, stem cells and umbilical cord, excluding umbilical cord progenitor cells.’

In the context of this article, the removal and/or withdrawal of the following from a living person therefore requires ministerial authorisation: • Embryonic tissue (from conception to 8 weeks of gestation) • Fetal tissue (from 9 weeks following conception to birth) • Stem cells • Placenta and umbilical cord.

PLURIPOTENT STEM CELLS Specifically excluded from this requirement are umbilical progenitor cells. The reason for this exclusion probably relates to the regulator’s understanding that stem cells from cord blood used in HSCT are limited to progenitor cells. There are, however, more primitive stem cells in cord blood, which are not progenitors that are likely to contribute to the success of engraftment following transplantation, as well as non-haematopoietic stem cells.[5] It is therefore understood that the removal and/or withdrawal of these cells would also require ministerial authorisation, since they are not specifically excluded. Since it is at present not possible to separate progenitors from the other stem cells on a routine basis, we would therefore interpret this to mean that removal and/or withdrawal of cord blood requires ministerial authorisation.

Research on embryos in the stem cell context A human embryo is the product of a fertilised egg, from the zygote until the fetal stage[6] or ‘the developing organism from fertilization to the end of the eighth week.[7] A further distinction is made for the period from fertilisation until 14 days which is referred to as the pre-embryonic (or pre-implantation) stage.[8] Fourteen days after fertilisation also marks the stage at which an embryo begins to develop a nervous system.[9] In 2002 the House of Lords in the UK published a report on stem cell research.[10] Chapter 4 which deals with ‘The Status of the Early Embryo’ is in line with the previous recommendations of the 1984 Warnock Committee Report[11] and concludes that ‘Whilst respecting the deeply held views of those who regard any research involving the destruction of a human embryo as wrong and having weighed the ethical arguments carefully, the Committee is not persuaded, especially in the context of the current law and social attitudes, that all research on early human embryos should be prohibited … If the respect to be accorded to an embryo increases as it develops, this is a gradual process and it may be difficult to establish precisely the point of transition from one stage to the next. The [Human Fertilisation and Embryology] 1990 Act established 14 days as the limit for research on early embryos. Fourteen days has an objective justification insofar as it represents the stage at which the primitive streak, the precursor of the development of a nervous system, begins to appear. This limit seems to have been widely accepted, and the research done under the Act under licence from the HFEA [Human Fertilisation and Embryology Authority] has attracted very little criticism from those who accept the case for research on early embryos. We have received no evidence to suggest that,

Fig. 3. Induced pluripotent stem (iPS) cells. iPS cells are derived from differentiated human somatic cells which are reprogrammed (dedifferentiated) to a pluripotent state. This is achieved by the introduction and expression of 4 transcription factors – Oct4, Sox2, Klf4 and c-Myc – into the somatic cells of interest.

if research on human embryos is to continue, there should be a different limit. In point of fact the stage at which stem cells need to be extracted for research is very much earlier than that – at the blastocyst stage – when the early embryo is still smaller than a pinhead. The Committee considers that 14 days should remain the limit for research on early embryos’. The 14 day limit was also recommended by the Waller Committee in Victoria, Australia, in 1984.[12] With regard to definitions in the South African legislation, an embryo is defined in the NHA as ‘a human offspring in the first eight weeks from conception’ (Annexure). Use of the word offspring is not appropriate and we would suggest replacing the definition with ‘the early stages of human growth and development, from conception to the eighth week’.

Removal and/or withdrawal of tissue from a living human embryo requires ministerial authorisation. Tissue is defined in the NHA as ‘human tissue, and includes flesh, bone, a gland, an organ, skin, bone marrow or body fluid, but excludes blood or a gamete’, and in the Regulations Relating to Tissue Banks[13] as ‘a functional group of cells. The term is used collectively in the Regulations to indicate both cells and tissue’.

Subsection 57(4) of Chapter 8 of the NHA stipulates that ‘[t]he Minister may permit research on stem cells and zygotes which are not more than 14 days old on a written application and if (a) the applicant undertakes to document the research for record purposes; and (b) prior consent is obtained from the donor of such stem cells or zygotes’. It is presumed that ‘cells and zygotes’ should be interpreted as a pre-embryo, as defined above. The Act is however silent on research on embryos from 14 days to 8 weeks of gestation.

Section 57(3) provides that ‘[n]o person may import or export human zygotes or embryos without the prior written approval of the Minister’.

In summary, removal and/or withdrawal of tissue from a living human embryo requires ministerial authorisation. It is not clear, however, whether ‘use’ of this tissue, once removed from a 3-8 week embryo, requires ministerial authorisation. Irrespective, such ‘use’ will require the approval of a registered research ethics committee.

Somatic cell nuclear transfer The procedure of SCNT can be described as the removal of the chromosomes (constituted as the meiotic spindle complex) from an oocyte, followed by the transfer and fusion of a donor somatic cell nucleus to the enucleated oocyte. The manipulated oocyte is then artificially activated which should induce subsequent development of the embryo (Fig. 4).

Fig. 4. Somatic cell nuclear transfer (SCNT). SCNT involves the removal of the chromosomes (constituted as the meiotic spindle complex) from an oocyte, followed by the transfer and fusion of a donor somatic cell nucleus to the enucleated oocyte. The manipulated oocyte is then artificially activated which should induce subsequent development of the embryo.

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PLURIPOTENT STEM CELLS SCNT is currently being performed in several laboratories worldwide for the purpose of creating human stem cells. In the UK for example, human SCNT research is legal and in 2001 was incorporated into the Human Fertilisation and Embryology Act 1990 (HFEA). However, before performing SCNT it is necessary to obtain permission from the HFEA. In the USA, SCNT research is also legal but may not be funded by the federal government as a result of the Dickey-Wicker Amendment bill passed in 1995. The Department of Health and Human Services and the National Institutes of Health prohibits the use of funds for research studies involving the creation of human embryos and the destruction thereof. SCNT research aimed at producing human ES cells may nonetheless be legally performed when funded by private or non-governmental organisations.

Strict regulation of human SCNT research should be maintained by registered research ethics committees, as well as by ethical guidelines that have been set by the US National Academy of Science, the International Society for Stem Cell Research (ISSCR), and the American Society for Reproductive Medicine.[14] As reviewed by Cervera and Mitalipov,[15] there are several ethical and legal issues associated with SCNT, one of the most important of which is access to human oocytes. The ideal approach would be to identify donors willing to provide oocytes for research without any reimbursement. According to one study, however, women are simply not prepared to undergo ovarian stimulation and invasive oocyte retrieval without being reimbursed for their efforts.[16] The ISSCR ‘Position Statement on the Provision and Procurement of Human Eggs for Stem Cell Research’[17] recommends that ‘[p]aying (in cash or kind) women for providing eggs for research is ethically justifiable as a means of compensating them for their time, inconvenience, willingness to accept some risks, and reimbursement for out-of-pocket expenses.

This is not a payment for the eggs themselves’. Other observations and/ or recommendations include the unethical nature of using financial incentives to induce donation, the need for review by a registered research ethics committee, the need to separate fertility treatments from egg donation, the need for standard operating procedures in accredited institutions and for donor follow-up after donation, and vigilance with regard to cross-border donation and trafficking. Local laws regulating compensation for oocyte donors may also govern the procurement of human oocytes for research purposes. In California, for example, patients donating oocytes for research purposes are covered for certain expenses but are not reimbursed for ‘time, effort and inconvenience’. In Oregon, on the other hand, research oocyte donors are fully compensated in a manner that is equal to reproductive oocyte donors. [18] With regard to the situation in South Africa, subsection 60(1)(a) of Chapter 8 of the NHA, entitled ‘Payment in connection with the importation, acquisition or supply of tissue, blood, blood products or gametes’, stipulates that ‘a hospital or an institution contemplated in section 58(1)(a), a person or an institution contemplated in section 63 and an authorised institution or, in the case of tissue or gametes imported or exported in the manner provided for in the regulations, the importer or exporter concerned, may receive payment in respect of the acquisition, supply, importation or export of any tissue or gamete for or to another person for any of the purposes contemplated in section 56 or 64’. This is further detailed in subsections (2), (3), (4) and (5) as follows: ‘(2) The amount of payment contemplated in subsection (1) may not exceed an amount which is reasonably required to cover the costs

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involved in the importation, export, acquisition or supply of the tissue, gamete, blood or blood product in question.

(3) This section does not prevent a health care provider registered with a statutory health professional council from receiving remuneration for any professional service rendered by him or her.

(4) It is an offence for a person (a) who has donated tissue, a gamete, blood or a blood product to receive any form of financial or other reward for such donation, except for the reimbursement of reasonable costs incurred by him or her to provide such donation; and (b) to sell or trade in tissue, gametes, blood or blood products, except as provided for in this Chapter.

(5) Any person convicted of an offence in terms of subsection (4) is liable on conviction to a fine or to imprisonment for a period not exceeding five years or to both a fine and such imprisonment.’

Further guidance regarding the legal position relating to egg donation in South Africa is found in the Regulations Relating to Artificial Fertilisation of Persons.[19] A gamete donor ‘means a living person from whose body a gamete or gametes are removed or withdrawn, for the purpose of artificial fertilisation’. With regard to compensation, clause 4 states that ‘[a] person from whose body a gamete has been removed or withdrawn may be reimbursed for any reasonable expenses incurred by him or her in order to donate a gamete as contemplated in section 60(4)(a) of the (National Health) Act’. Clauses 6 and 7 stipulate that only six children may be conceived through artificial fertilisation from a single gamete donor.

It should be noted that the NHA and the regulations are silent regarding egg donation for research purposes.

Further details regarding payment are provided in the 2008 guidelines of the Southern African Society for Reproductive Medicine and Gynaecological Endoscopy (SASREG).[20] With regard to payment of oocyte donors, the guidelines state that ‘[m]onetary compensation of the donor should reflect the time, inconvenience, financial costs to the donor – e.g. travel, loss of income and childcare costs, physical and emotional demands and risks associated with oocyte donation and should be at a level that minimizes the possibility of undue inducement of donors and the suggestion that payment is for the oocytes themselves. The monetary compensation should not be predicated on the clinical outcome (no. of oocytes or pregnancy outcome) but rather on fair compensation for the procedure of donating eggs […] Donors should only receive financial compensation via fertility clinics and not receive any compensation directly from the recipients or other third parties’. In an amendment of 25 November 2014 it is stipulated that ‘[e]gg donors should not be compensated more than R7 000 per procedure from 1 January 2015’.[21] As a result of the ethical and financial limitations related to reimbursement of oocyte donors, alternative sources of human oocytes have been investigated for SCNT research. Immature oocytes, which are generally discarded in assisted reproductive procedures, are voluntarily donated by patients for research purposes. However, in vitro maturation, fertilisation, and subsequent development of these immature oocytes to the blastocyst stage are highly compromised following SCNT, and are therefore not appropriate for optimisation of the SCNT procedure.[22,23] It should be noted that the use of high-quality human oocytes in SCNT does not guarantee successful embryo development to the

PLURIPOTENT STEM CELLS blastocyst stage. In a study conducted by Noggle and colleagues,[24] successful blastocyst development and subsequent isolation of ESCs was only observed in those embryos that had somatic cells transferred to non-enucleated oocytes. This observation may have implied that molecules essential for proper reprogramming of the somatic cell nucleus might be removed during enucleation, which are supposedly retained by the presence of the oocyte’s own chromosomes. Another study that observed early failure in monkey SCNT embryo development, also assumed that the cause was related to the removal of reprogramming factors during enucleation possibly linked to the oocyte’s chromosomes.[25] Subsequent studies have however proven otherwise, namely that the oocyte’s chromosomes are not a prerequisite for the successful reprogramming of the somatic cell nuclear genome.[26] Nevertheless, many studies encourage that each step in SCNT be thoroughly optimised and adapted specifically for human oocytes. In summary, a major drawback related to rigorous testing on human oocytes is the requirement of a large number of good quality human oocytes, which remains limited.[11] From an ethical point of view, the intentional creation of embryos using SCNT is condemned for a variety of reasons. It is seen to diminish human individuality and integrity, and the freedom, identity and dignity of the human person (in the sense that many identical copies of the same DNA may be created). It could also be viewed as impacting on human reproductive autonomy, as an embryo is created with only one genetic parent to whom the embryo would be genetically identical. Researchers should be cognizant of these concerns, which are fundamental to our understanding of humanity, human identity, the inviolability of the human person, human reproduction and human dignity. Global consensus on the ban of reproductive cloning in the form of the UN Declaration on Human Cloning (2005)[27] has unfortunately cast a shadow on the use of SCNT in the context of ‘therapeutic cloning’, incorrectly equated with ‘reproductive cloning’.

Reproductive and therapeutic cloning Blastocysts derived by SCNT can be utilised in two ways (Fig. 5). In the first, the blastocyst is placed in the uterus of a surrogate mother and if

development occurs to term, the resulting offspring will be identical to the somatic cell donor and will have been derived by a process referred to as ‘reproductive cloning’. In the second, cells derived from the ICM of the blastocyst are grown in tissue culture to form ES cells.

This process is referred to as ‘therapeutic cloning’ since the ES cells are autologous as the nuclear genome of these cells is identical to that of the somatic cell donor. (Note that the mitochondrial genome will be a mosaic between the oocyte donor and the somatic cell donor). Use of these cells in the donor would not require immunosuppression, as would be the case if the cells were allogeneic.

Reproductive cloning of a human being is defined in subsection 57(6)(a) of Chapter 8 of the NHA as ‘the manipulation of genetic material in order to achieve the reproduction of a human being and includes nuclear transfer or embryo splitting for such purpose’ (Annexure). We would suggest replacing this with ‘the manipulation of cells, gametes, zygotes or embryos or genetic material derived therefrom in order to achieve reproduction of a human being and includes but is not limited to nuclear transfer and embryo splitting’.

Subsection 57(1) of Chapter 8 of the NHA, entitled ‘Prohibition of reproductive cloning of human beings’, stipulates that a person may not ‘(a) manipulate any genetic material, including genetic material of human gametes, zygotes or embryos; or (b) engage in any activity, including nuclear transfer or embryo splitting, for the purpose of the reproductive cloning of a human being.’

Therapeutic cloning is defined in section 57(6)(b) of Chapter 8 of the NHA as ‘the manipulation of genetic material from either adult, zygotic or embryonic cells in order to alter, for therapeutic purposes, the function of cells or tissues’ (Annexure). This definition is problematic as it is much broader and less specific than the recognised procedure for reproductive cloning, which as described above is SCNT. We would recommend the inclusion of SCNT in the definition.

In contrast to reproductive cloning, subsection 57(2) of Chapter 8 of the NHA provides that ‘[t]he Minister may, under such conditions as may be prescribed, permit therapeutic cloning utilising adult or umbilical cord stem cells’.

According to subsection 57(5) of Chapter 8 of the NHA, ‘[a]ny person who contravenes a provision of this section or who fails to comply therewith is guilty of an offence and is liable on conviction to a fine or to imprisonment for a period not exceeding five years or to both a fine and such imprisonment’.

In summary, reproductive cloning is banned in SA. Therapeutic cloning is permitted but requires ministerial authorisation since this involves ‘research on stem cells and zygotes which are not more than 14 days’. This is summarised in Table 2.

Embryonic stem cells Fig. 5. Reproductive and therapeutic cloning. Blastocysts derived by SCNT can be utilised in two ways. In the first, the blastocyst is placed in the uterus of a surrogate mother and if development occurs to term, the resulting offspring will have been derived by a process referred to as ‘reproductive cloning’. In the second, cells derived from the ICM of the blastocyst are grown in tissue culture to form ES cells. The nuclear genome of these cells is identical to that of the somatic cell donor. This process is referred to as ‘therapeutic cloning’.

Embryonic stem cells are derived from the ICM of the blastocyst.

In humans, the blastocyst is equivalent to a 5-day-old embryo.

The ICM, which consists of approximately 100 cells, is manually removed from the (pre-)embryo and is placed in tissue culture under specific conditions.[28] The resulting cells are termed ES cells and are pluripotent in nature.

Two methods can be used to obtain a blastocyst. The first is IVF and the second is SCNT (discussed above).

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PLURIPOTENT STEM CELLS There are several views as to when human life begins. These include: • at the moment of fertilisation • with the development of the first organ system (heart and blood vessels) • at the moment of perceived consciousness • from the moment the fetus is able to survive outside the uterus (22-24 weeks).

These perceptions may explicitly or implicitly influence considerations relating to the possible uses, creation and ‘destruction’ of human embryos for research purposes, more so when research activities involving the human embryo are legally defined. As described in the section on Research on embryos in the stem cell context above, the 14-day limit following fertilisation, after which embryos may not be permitted to develop further in vitro, is commonly accepted.

For those who believe that life begins at the moment of fertilisation, preparation of ES cells would be tantamount to destroying a human life. This is the source of the controversy surrounding ES cells.

Secondly, the source of these human embryos or ES cells is also relevant. For example, in the case of embryos, were they created solely for research purposes or were they excess embryos left over after IVF treatment? If not used and destined to be discarded in any event, a strong argument could be advanced that it may be morally justifiable to use them in medical research aimed at ultimately benefiting the greater collective.

From a legislative point of view, the preparation of human ES cells and all research involving these cells requires ministerial authorisation in SA.

Induced pluripotent stem cells Induced pluripotent stem cells are derived from differentiated human somatic cells which are reprogrammed (dedifferentiated) to a pluripotent state. This is achieved by the introduction and expression of four transcription factors – Oct4, Sox2, Klf4 and c-Myc – into the somatic cells of interest.[29] Reprogramming is a universal process, and has been done in mesodermal, endodermal and ectodermal derivatives including fibroblasts, lymphocytes, liver, stomach, beta cells and neural progenitor cells from a variety of species.

Like ES cells, human iPS cells have the potential to develop into any of the body’s cell types and are therefore pluripotent in nature. iPS cells are however easier to produce than ES cells, and are not associated with the same controversial embryonic source, as the procedure does not involve the use of human embryos or oocytes.

Obtaining somatic cells (e.g. through a skin biopsy) is also noninvasive, compared to the donation of oocytes used in the SCNT procedure.

One of the primary legal concerns associated with the procurement of iPS cells is the issue of the (genetic) privacy of the cell donor. Unauthorised or inappropriate disclosure of the donor’s genetic information holds specific ethical, legal, social and economic risks. Researchers should take special care to protect the privacy interests of donors, for example by measures that will control cross-referencing of information to public databases. The issue of incidental findings also arises, which concerns the inadvertent discovery of a donor’s genetic predisposition to a specific condition or disease by the researcher. The question arises as to how to deal with these findings.[30] Informed consent, specifically the withdrawal

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of consent, poses another challenge. iPS cell lines may also be used indefinitely for future research, which poses an obstacle with regard to voluntary informed consent by research participants. For example, with regard to the various uses of cell lines, donors may morally object to the derivation of human gametes or the creation of human-animal chimeras. The conventional rule that a research participant may withdraw his or her participation at any time during the research is another challenge in this context. If an iPS cell line has been created, may a donor withdraw his or her consent to participate in the research? If so, the consequences for the relevant researcher may be far-reaching.[30] Further concerns that have been mentioned relate to possible downstream uses of the iPS cell derivates, which may include the genetic modification of the cells; large scale genomic sequencing; the sharing of cell lines among researchers; the commercialisation of applications involving the cells; and the possibility of deriving gametes in vitro from IPS cells.[31] With regard to the derivation of gametes, the potential of iPS cells to differentiate into both male and female germ cells in different species, including the development of gametes and offspring in mice, has already been demonstrated.[32,33] This gives rise to intricate legal and ethical issues relating to the sequence and process of reproduction and genetic parentage, not to mention informed consent issues, concerns regarding cloning, as well as the potential to create an embryo by donors who may have no knowledge of such possibility or attempt.

Genome editing of pre-implantation embryos Genome editing is the precise and intentional modification of nucleotide sequences in a genome, and has been used successfully in stem cells (including pluripotent stem cells) and adult somatic cells. DNA is inserted, removed or replaced at specific predetermined sites using artificially engineered nucleases or ‘molecular scissors’. Engineered nucleases include zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9. The ability to treat and/or cure human diseases such as HIV/AIDS, haemophilia, sickle-cell anaemia and several forms of cancer using this technology has generated a great deal of excitement. However, the ability to alter the genome in gametes (sperm, eggs), zygotes (fertilised eggs) and early embryos has raised a great deal of concern.[34, 35] This is in part due to the limited knowledge, unpredictable nature and unintended consequences accompanying ‘on-target’ intended effects, as well as ‘off-target’ effects, which involve unintended gene editing at sites other than those targeted. These changes will be passed on to subsequent generations and the potential consequences to the individual, their families and society as a whole will need to be carefully considered. In addition, there is the fear that unscrupulous individuals may move towards unsafe or unethical uses of the technology.

Liang et al.[36] have recently published the first set of experiments performed on early human embryos. They found that although the target gene (b-globin or HBB) was effectively cleaved, the efficiency was low and the resultant embryos were mosaic. Off-target effects were also observed. These findings confirm and highlight the need

PLURIPOTENT STEM CELLS to proceed with great caution in human gametes, zygotes and embryos.

In a highly laudable form of ‘self-regulation’, the global scientific, medical, legal and ethics communities have recommended that the use of these technologies in gametes, zygotes and early embryos in humans be put on hold until there is a greater appreciation of their consequences. The community has called for regulatory measures to be put into place, for the initiation of an open public debate and for open and transparent research which is subjected to peer review.

Council and approval from a registered research ethics committee (which implies peer review). Furthermore, patients should not have to pay for these experimental forms of treatment.

Clinical translation

1. Bianconi E, Piovesan A, Facchin F, et al. An estimation of the number of cells in the human body. Ann Hum Biol 2013;40(6):463-471. [http://dx.doi.org/10.3109/0301 4460.2013.807878] 2. Nobel Prize.org. The Nobel Prize in Physiology or Medicine. Sweden: Nobel Prize. org, 2012. http://www.nobelprize.org/nobel_prizes/medicine/laureates/2012/ press.html (accessed 14 June 2015).

3. Republic of South Africa. National Health Act 61. Government Gazette 2003.

4. Republic of South Africa. Medicines and Related Substances Control Act 101.

Government Gazette 1965.

5. Phuc PV, Ngoc VB, Lam DH, et al. Isolation of three important types of stem cells from the same samples of banked umbilical cord blood. Cell Tissue Bank 2012;13(2):341-351. [http://dx.doi.org/10.1007/s10561-011-9262-4] 6. Wikipedia Foundation. Embryo definition. San Francisco: Wikipedia Foundation. https://en.wikipedia.org/wiki/Embryo (accessed 14 June 2015).

7. Miller-Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health. 7th ed. Philadelphia: WB Saunders, 2003. http://medical-dictionary. thefreedictionary.com/embryo (accessed 14 June 2015).

8. Schoenwolf GC, Bleyl SB, Brauer PR, et al. Larsen’s Human Embryology. 4th ed.

Philadelphia: Churchill Livingstone/Elsevier, 2009.

9. Wellcome Trust. Wellcome Trust Glossary. London: Wellcome Trust. http://www. wellcome.ac.uk/About-us/Policy/Spotlight-issues/Human-Fertilisation-andEmbryology-Act/Stem-cell-basics/WTD040065.htm (accessed 14 June 2015).

10. www.parliament.uk. House of Lords Stem Cell Research Report; chapter 4: The status of the early embryo. London: www.partliament.uk, 2001. http://www. parliament.the-stationery-office.co.uk/pa/ld200102/ldselect/ldstem/83/8305. htm#a24 (accessed 25 June 2015).

11. Department of Health and Social Security. Warnock Report of the Committee of Inquiry into Human Fertilisation and Embryology. London: Her Majesty’s Stationery Office, 1984. http://www.hfea.gov.uk/docs/Warnock_Report_of_the_ Committee_of_Inquiry_into_Human_Fertilisation_and_Embryology_1984.pdf (accessed 25 June 2015).

12. Victoria [Australia]. Committee to Consider the Social, Ethical and Legal Issues arising from In Vitro Fertilization, Report on the disposition of embryos produced by in vitro fertilization (Chairman, Louis Waller). Melbourne: Atkinson Government Printer, 1984.

13. Republic of South Africa. Regulations Relating to Tissue Banks in Government Notice R182, Government Gazette 35099 of 2 March 2012. Pretoria: Government Printer, 2012.

14. Hyun I. Moving human SCNT research forward ethically. Cell Stem Cell 2011;9(4):295-297. [http://dx.doi.org/10.1016/j.stem.2011.08.001] 15. Cervera RP, Mitalipov S. Primate and Human Somatic Cell Nuclear Transfer. In: Biology and Pathology of the Oocyte - Role in Fertility, Medicine and Nuclear Reprograming.Trounson A, Gosden R, Eichenlaub-Ritter U, eds. Cambridge: Cambridge University Press, 2013:274-284.

16. Egli D, Chen AE, Saphier G, et al. Impracticality of egg donor recruitment in the absence of compensation. Cell Stem Cell 2011;9(4):293-294. [http://dx.doi. org/10.1016/j.stem.2011.08.002] 17. Haimes E, Skene L, Ballantyne AJ, et al. ISSCR position statement on the provision and procurement of human eggs for stem cell research. Cell Stem Cell 2013;12(3):285-291. [http://dx.doi.org/10.1016/j.stem.2013.02.002] 18. Zacher A. Oocyte donor compensation for embryonic stem cell research: An analysis of New York’s payment for eggs program. Albany Law Journal of Science and Technology 2011;21:323.

19. Republic of South Africa. Regulations relating to Artificial Fertilisation of Persons, Government Notice R175, Government Gazette 35099 of 2 March 2012. Pretoria: Government Printer, 2012.

20. Southern African Society of Reproductive Medicine and Gynaecological Endoscopy South African Society of Reproductive Science and Surgery.

Guidelines for Gamete Donation. South Africa: SASREG, 2008 http://www. fertilitysa.org.za/Guidelines/ReproductiveMedicine/2008%20GUIDELINES%20 FOR%20GAMETE%20DONATION.pdf (accessed 14 June 2015).

21. Southern African Society of Reproductive Medicine and Gynaecological Endoscopy South African Society of Reproductive Science and Surgery. Amendment to 2008

The clinical translation of research conducted on pluripotent stem cells is clearly of immense interest. Safety issues relate in part to the ability of these cells to divide in an autonomous manner, and the ability of these cells to form tumours has been well described.

With regard to ES cells (irrespective of their mode of derivation), clinical trials have to date been limited. One clinical trial has been conducted for spinal cord injury using ES cell-derived oligodendrocyte precursors. This trial was terminated prematurely after treating five patients and has been the subject of much debate.[37] Long-term follow-up of these patients has revealed no clinical improvement or adverse effects related to the treatment. Other clinical trials have utilised ES cell-derived retinal pigment epithelial (RPE) cells for the treatment of a variety of retinal disorders, including age-related macular degeneration. Results to date have revealed possible clinical improvement with no adverse effects related to the treatment.[38] With regard to iPS cells, which are a much more recent discovery than ES cells, a single clinical trial is underway for age-related macular de­gen­eration using iPS cell-derived RPE cells.[39] It is likely, however, that an increasing number of clinical trials will follow, including the use of iPSderived dopamine-releasing neurons in patients with Parkinson’s disease.

The question arises as to whether pluripotent cells should be governed by the same regulations that apply to other cell-based products given their unique characteristics and the processes used for their derivation. With regard to their derivation, ES cells will be governed by legislation that governs the use of human embryos. This does not apply to iPS cells. With regard to clinical trials, both cell types and their derivatives would be subjected to the same rules that apply to all clinical trials. In the SA context, these are clearly spelled out in the general regulations made in terms of the Medicines and Related Substances Control Act 101 of 1965.[40]

Conclusion With the exception of reproductive cloning, which is banned globally, research on human embryos including SCNT, the derivation of ES cells and therapeutic cloning are all permissible according to SA legislation, but according to the NHA and regulations thereto, require ministerial authorisation. Specific matters on which the NHA is silent include egg donation for research purposes, iPS cells and genome editing of preimplantation embryos.

With regard to the use of pluripotent cells or their derivatives for therapeutic purposes, since this is still experimental in nature it would be governed by the rules that apply to clinical trials. These cells would fall under the section of ‘biological medicines’ in the Guidelines to the Registration of Medicines,[41] to be read in conjunction with the Medicines and Related Substances Act and its regulations. This includes, among others, registration with the Medicines Control

Funding. This research and its publication is the result of funding provided by the Medical Research Council of South Africa in terms of the MRC’s Flagships Awards Project SAMRC-RFA-UFSP-01-2013/STEM CELLS

References

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29

PLURIPOTENT STEM CELLS Guidelines for Gamete Donation. South Africa: SASREG, 25 November 2014 http:// www.fertilitysa.org.za/Guidelines/ReproductiveMedicine/Egg%20donor%20 compensation%20-%20November%202014.pdf (accessed 14 June 2015).

22. Heindryckx B, De Sutter P, Gerris J, et al. Embryo development after successful somatic cell nuclear transfer to in vitro matured human germinal vesicle oocytes.

Human Reprod 2007;22(7):1982-1990.

23. Tachibana M, Sparman M, Woodward J, et al. Derivation of human embryonic stem cells from discarded immature oocytes. International Society for Stem Cell Research (ISSCR), Tenth Annual Meeting. Yokohama, Japan June 13-16, 2012.

24. Noggle S, Fung HL, Gore A, et al. Human oocytes reprogram somatic cells to a pluripotent state. Nature 2011;478(7367):70-75. [http://.dx.doi.org/10.1038/ nature10397] 25. Simerly C, Dominko T, Navara C, et al. Molecular correlates of primate nuclear transfer failures. Science 2003;300(5617):297. [http://dx.doi.org/10.1128/ science.1082091] 26. Byrne J, Pedersen D, Clepper L, et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 2007;450(7168):497-502. [http://dx.doi. org/10.1038/nature06357] 27. United Nations. United Nations Declaration on Human Cloning. GA Res., UNGAOR, 59th Sess., UN Doc. A/280 (2005). http://www.nrlc.org/uploads/international/UNGADeclarationHumanCloning.pdf (accessed 14 June 2015).

28. Reubinoff BE, Pera MF, Fong CY, et al. Embryonic stem cell lines from human blastocysts: Somatic differentiation in vitro. Nat Biotechnol 2000;18(4):399–404. [http://dx.doi.org/10.1038/74447] 29. Yamanaka S. Strategies and new developments in the generation of patientspecific pluripotent stem cells. Cell Stem Cell 2007;1(1):39-49. [http://dx.doi. org/10.1016/j.stem.2007.05.012] 30. Zarzeczny A, Scott C, Hyun I, et al. iPS cells: Mapping the policy issues. Cell 2009;139(6):1032-1037. [http://dx.doi.org/10.1016/j.cell.2009.11.039]

31. Pardo R, Calvo F. Attitudes toward embryo research, worldviews, the moral status of the embryo frame. Science Communication 2008;30(1):8-47. [http://dx.doi. org/10.1177/1075547008319432] 32. Easley CA 4th, Phillips BT, McGuire MM, et al. Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Rep 2012;2(3):440446. [http://dx.doi.org/10.1016/j.celrep.2012.07.015] 33. Ishii T. Human iPS cell-derived germ cells: Current status and clinical potential. J Clin Med 2014;3:1064-1083.

34. Baltimore D, Berg P, Botchan M, et al. A prudent path forward for genomic engineering and germline gene modification. Science 2015;348(6230):36-38. [http://dx.doi.org/10.1126/science.aab1028] 35. Lanphier E, Urnov F, Haecker SE, et al. Don’t edit the human germ line. Nature 2015;519(7544):410-411. [http://dx.doi.org/10.1038/519410a] 36. Liang P, Xu Y, Zhang X, et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell 2015;6(5):363-372. [http://dx.doi.org/10.1007/ s13238-015-0153-5] 37. Scott CT, Magnus D. Wrongful termination: Lessons from the Geron clinical trial. Stem Cells Transl Med 2014;3(12):1398-1401. [http://dx.doi.org/10.5966/sctm.2014-0147] 38. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: Follow-up of two open-label phase 1/2 studies. Lancet 2015;385(9967):509-516. [http://dx.doi.org/10.1016/S0140-6736(14)61376-3] 39. Reardon S, Cyranoski D. Japan stem-cell trial stirs envy. Nature 2014;513(7518):287288. [http://dx.doi.org/10.1038/513287a] 40. Republic of South Africa. Government Notice R510, Government Gazette 24727 of 10 April 2003, as amended. Pretoria: Government Printer, 2003.

41. Republic of South Africa. Guidelines to the Registration of Medicines, Medicines Control Council, August 2012. http://www.kznhealth.gov.za/research/mccinfo. pdf (accessed 14 June 2015).

Annexure Definitions from the National Health Act and Regulations Name

Definition

Source

Comment / proposal

DNA

deoxyribonucleic acid, which is a nucleic acid, composed of building blocks called nucleotides

Regulations relating to the use of human biological material (No. R. 177)

Proposal – include: the sub-cellular component that contains human genetic information

deoxyribose nucleic acid which is a nucleic acid composed of building blocks called nucleotides

Regulations relating to the import and export of human tissue, blood, blood products, cultured cells, stem cells, embryos, fetal tissue, zygotes and gametes (No. R. 181)

chromosome

a thread-like structure made up of DNA found in the nucleus of all cells

Regulations relating to the use of human biological material (No. R. 177)

gamete

either of the two generative cells essential for human reproduction

National Health Act (No. 61 of 2003)

oocyte

developing human egg cell

National Health Act (No. 61 of 2003)

the female gamete

Regulations relating to artificial fertilisation of persons (No. R. 175)

sperm

the male gamete

Regulations relating to artificial fertilisation of persons (No. R. 175)

zygote

the product of the union of a male and a female gamete

National Health Act (No. 61 of 2003)

polar body

a product that is formed during the development of the female gamete (during meiosis), which contains little cytoplasm and a haploid number of chromosomes

Regulations relating to the use of human biological material (No. R. 177)

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Note: only visible during cell division

Not defined in the Act

PLURIPOTENT STEM CELLS Annexure (continued) Definitions from the National Health Act and Regulations Name

Definition

Source

Comment / proposal

gonad

human testis or human ovary

National Health Act (No. 61 of 2003)

embryo

a human offspring in the first 8 weeks from conception

National Health Act (No. 61 of 2003)

Use of the word ‘offspring’ is inappropriate.

Proposal – replace with: the early stages of human growth and development, from conception to the eighth week

a human offspring in the first 8 weeks of conception

Regulations relating to the import and export of human tissue, blood, blood products, cultured cells, stem cells, embryos, fetal tissue, zygotes and gametes (No. R. 181)

Use of the word ‘offspring’ is inappropriate.

Use of the phrase ‘of conception’ is inappropriate as conception is generally accepted as the moment of fertilisation

embryonic tissue

tissue from an embryo

Regulations relating to the import and export of human tissue, blood, blood products, cultured cells, stem cells, embryos, fetal tissue, zygotes and gametes (No. R. 181)

blastocyst

a pre-implantation embryo consisting of an outer layer, which forms the placenta and a 30 to 200-cell inner cell mass, which develops into the fetus

Regulations relating to artificial fertilisation of persons (No. R. 175)

fetus

a human offspring from 8 weeks after conception until birth

Regulations relating to the use of human biological material (No. R. 177)

Use of the word ‘offspring’ is inappropriate

a human offspring from 8 weeks after conception until birth

Regulations relating to the import and export of human tissue, blood, blood products, cultured cells, stem cells, embryos, fetal tissue, zygotes and gametes (No. R. 181)

Use of the word ‘offspring’ is inappropriate

fetal tissue

tissue from a fetus

Regulations relating to the import and export of human tissue, blood, blood products, cultured cells, stem cells, embryos, fetal tissue, zygotes and gametes (No. R. 181)

primordial germ cells

stem cells found in the gonad of a fetus capable of becoming ova or sperm

Regulations relating to the use of human biological material (No. R. 177)

embryonic stem cell

any cell from the 30-200 inner cell mass of the blastocyst

Regulations relating to the use of human biological material (No. R. 177)

reproductive cloning of a human being

the manipulation of genetic material in order to achieve the reproduction of a human being and includes nuclear transfer or embryo splitting for such purpose

National Health Act (No. 61 of 2003) Section 57(6)(a)

Proposal – replace with: the manipulation of cells, gametes, zygotes or embryos or genetic material derived therefrom in order to achieve the reproduction of a human being and includes but is not limited to nuclear transfer and embryo splitting

therapeutic cloning

the manipulation of genetic material from either adult, zygotic or embryonic cells in order to alter, for therapeutic purposes, the function of cells or tissues

National Health Act (No. 61 of 2003) Section 57(6)(b)

Definition should include somatic cell nuclear transfer

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PLURIPOTENT STEM CELLS

Mitochondrial transfer: Ethical, legal and social implications in assisted reproduction A S Reznichenko,1,2 MSc; C Huyser,1 PhD; M S Pepper,2 MB ChB, PhD, MD 1 2

Department of Obstetrics and Gynaecology, Steve Biko Academic Hospital, University of Pretoria, South Africa Department of Immunology and Institute for Cellular and Molecular Medicine, Faculty of Health Sciences, University of Pretoria, South Africa

Corresponding author: A S Reznichenko (sashrez@gmail.com)

Diseases resulting from mutations in mitochondrial DNA (mtDNA) are inherited by all offspring through the maternal lineage. Multiple organs are severely affected, no preventative treatments are available and most patients experience a poor quality of life or early death. With developments in mitochondrial transfer techniques, hope for preventing transmission of mutated mtDNA onto offspring is emerging. Many ethical issues have been raised regarding such treatments, which involve transfer of nuclear material into donated oocytes with healthy mitochondria, or the introduction of healthy donor mitochondria into affected oocytes. Blastomere, ooplasmic, pronuclear and spindle transfer have been explored. Ethical concerns relate to (a) the alteration of germ line genetics and (b) the dilemma of children inheriting DNA material from three instead of two parents. In contrast to gene therapy, where only the DNA of the treated individual is altered, these techniques involve the introduction of foreign mtDNA into the germ line that will be inherited by all children in downstream generations.

Mitochondrial transfer has also been closely associated with reproductive cloning, which is regulated differently worldwide. Children born from these techniques might experience an identity crisis. Although three gametes are needed to produce a healthy embryo in this scenario, the child will inherit all nuclear DNA from the intending parents, while only inheriting mtDNA from the donor. Social and scientific values must be considered when introducing new healthcare technology. Many believe that some assisted reproductive technology techniques go beyond the limits of acceptable medical intervention. But who ultimately decides what is acceptable? We address the ethical and social issues surrounding this emerging new technology, legal developments regarding its clinical introduction in the UK and the USA, the future impact on technique and patient management, and relevant legislation in South Africa.

S Afr J BL 2015;8(2 Suppl 1):32-35. DOI:10.7196/sajbl.8002

Mitochondrial DNA (mtDNA) diseases are inherited maternally by both male and female offspring, since all mitochondria are derived from the oocyte cytoplasm.[1] Most symptoms result in severe disability as the muscles, heart and other vital organs, which require high cellular energy production, are heavily affected. Currently, treatments for such syndromes are limited and supportive, aiming to hinder progression of the disease, rather than restorative.[2] The most severely affected patients die very young having lived a very poor quality of life.[3,4] Alternative therapies are needed, including those which are preventative. However, with developments in mitochondrial transfer techniques many ethical issues have been raised in the health and public sectors regarding these novel treatment options.

Many papers have provided insight into possible cures for human mtDNA disorders via transfer of nuclear material into donated oocytes with healthy mitochondria, or the introduction of healthy donor mitochondria into the affected oocytes, using assisted reproductive technology (ART) techniques involving micromanipulation. These treatments could potentially prevent transmission of mitochondrial disease from an affected or carrier mother to her offspring. Spindle[5] and ooplasmic transfer[6,7] pre-fertilisation, and pronuclear[8] and blastomere nucleus transfer[9] post-fertilisation, have been explored to achieve this. Data from primate and human oocytes have shown spindle (Fig. 1a) and pronuclear transfer (Fig. 1b) to be the most viable thus far.[5,8,10-12] We address the ethical concerns that surround these

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concepts, discuss the legal positions in the UK, USA and South Africa, and propose the future clinical management of these techniques.

Alteration of germ line genetics Mitochondrial transfer has been closely associated with reproductive cloning because these technologies involve alteration of germ line genetics. Unlike gene therapy, in which only the DNA of the individual subjected to the treatment will undergo changes, these novel techniques involve the introduction of foreign mtDNA (from the donor oocyte) into the germ line, which will be inherited by offspring in later generations. A valid argument countering this concern is the fact that ooplasmic transfer has been applied clinically and given rise to the birth of several children.[6,7,13] Consequently, offspring of these female children can have completely different mtDNA make-up, especially if the bottleneck effect results in donor mtDNA comprising the higher proportion of total mtDNA in their oocytes. This means that there will be mostly donor mtDNA expansion in the embryo, and therefore subsequent generations. Surprisingly, to date, no long-term follow-up studies have been conducted on these children.[14] Regarding cloning concerns, which are often associated with mitochondrial transfer, reproductive adult cloning must be distinguished from reproductive embryo cloning. Adult cloning involves the transfer of adult (diploid) nuclear material into an enucleated oocyte. In contrast, the cell to be transferred in embryo cloning originates from an embryo.[15] The latter implies that the

PLURIPOTENT STEM CELLS Is ‘three-parent IVF’ a sensationalised term?

Fig. 1. Spindle(a) and pronuclear(b) transfer techniques.

ICSI = intracytoplasmic sperm injection. mtDNA = mitochondrial DNA. nDNA = nuclear DNA. IVF = in vitro fertilisation.

resulting child will be the first of its kind and not a clone of an already existing human.

However, many from the professional health and public sectors reject this technology.

Internationally, there are differing bioethical and legal regulations concerning human cloning (for reproductive, therapeutic and research purposes). A report in 2006[16] summarised these regulatory approaches from 16 countries. Cloning concerns are especially applicable to the blastomere nuclear transfer technique, where a blastomere is derived from an embryo that consists of several cells, not just a single cell as found during transfer of spindles or pronuclei (Fig. 1). Potentially, several blastomeres could

be transferred to several enucleated oocytes and give rise to genetically identical offspring.

The blastomeres of a single embryo could be used on different occasions resulting in ‘delayed’ twins.[17] This could be avoided by using one embryo per recipient oocyte, or one embryo per cycle. Alternatively, a multiple embryo transfer can be performed if multiple blastomeres of a single embryo are used for multiple recipient oocytes. Additionally, a completely new cycle could be initiated for each potential pregnancy.[17] The approach would be unique to each patient, depending on how many embryos are available and how many resultant embryos survive and implant.

The second ethical issue is the dilemma of children inheriting DNA material from three instead of two parents. The prevention of mtDNA disease transmission has been dubbed ‘three-parent IVF’. The general public have been led to believe that this will cause psychosocial problems for children born from these techniques, as they might experience an identity crisis. Three gametes are needed to produce a healthy embryo in this scenario.

However, a crucial point is that the child will inherit all nuclear DNA from the intending parents, while only inheriting the mtDNA from the donor. Mitochondrial DNA possesses less than 30 genes, while nuclear DNA encodes approximately 25 000 genes. Furthermore, mtDNA is highly conserved among humans (Professor Douglas C. Wallace, University of Pennsylvania, personal communication), and to an extent across species, as mitochondrial energy production is a universal function required by all living organisms. By scale of quantity (number of genes) and quality (gene function), it is misleading for a resultant child to be led to believe that its physical attributes are derived from three, not two, sets of parental DNA.[18] On the other hand, it can be questioned whether some phenotypic characteristics are highly accounted for by the mtDNA – physical strength or sports ability, for instance. Unfortunately, such an argument is not applicable in a clinical setting where a couple is unable to have a healthy child that can live to adulthood. Their primary concern is not whether their child will inherit the best mitochondria possible to become an olympic athlete. Furthermore, it has not been proven whether physical strength can be attributed to specific variants of mtDNA genes, mtDNA mutations with an evolutionary advantage, or number of mtDNA copies. Perhaps, physical ability is only partially or completely unrelated to the sequence or natural reserve of mtDNA. Nuclear genes and physical practice could be more responsible for this phenotype.

Other kinship forms that challenge the argument of loss of identity in children with ‘three’ parents include adoption, surrogacy and use of donor gametes (sperm or oocytes alike) or gestational carriers. Such children could experience the same psychosocial issues.[18] While not possessing DNA from three parents, they have the potential to experience a crisis in terms of how they fit into their families, as in

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PLURIPOTENT STEM CELLS theory they have more than two biological and social parents. Applying this sensationalism on a broader scale, would children born through embryo donation then have four parents? Nevertheless, researchers have suggested that if a paternal female relative is available and willing to donate oocytes for the mitochondrial transfer treatment, offspring will inherit paternal mtDNA and all nuclear DNA of the intending parents.

Thereby the child will theoretically not possess any ‘foreign’ DNA from a third party.[9] Additionally, excluding adoption, all cases have a genetic aspect involved. Use of donor gametes and surrogate mothers, of course, result in a complete difference of genetic material between the child and one of the intending parents, causing them to be biologically unrelated. With regard to the use of surrogacy or a gestational carrier, the development of the fetus does not take place in the intending mother’s uterus. This alteration of the developmental environment causes epigenetic alterations in the fetal DNA. In this way, the woman that carries the child makes an indirect genetic contribution to the child since epigenetic DNA changes do modify the child’s phenotype and can even cause disease.[19] On the grounds that adoption, fostering, step-parenting, surrogacy, and gamete donation are widely accepted in society today, the use of mitochondrial donors is only an extension of current forms of kinship. It seems unlikely that individuals born by these novel procedures would experience more or any psychosocial issues. Researchers conducting evaluations of donor conceived children consider that persons born through mitochondrial transfer techniques would better fit into the category of naturally conceived children, than donor conceived children, when it comes to their psychological wellbeing.[20] The mitochondrial donor should not necessarily be regarded as a second mother or parent to the resulting child, as this is refutable on both biological and legal principles (‘Mater semper certa est’). There is also evidence that individuals usually cope quite well with information regarding their origins (be they genetic, biological and/or social) provided that they are told at a relatively young age (during their pre- or primary school years) and in a controlled manner.[21] It is probably advisable for children born by preventative mtDNA disease techniques to be informed at an early age, and that this is reported to them with sufficient information about the procedures and relatively small genetic contribution from the donor.

Future management The Nuffield Council on Bioethics of the United Kingdom (UK)[22] has reviewed the novel micromanipulation techniques, which can be utilised for the prevention of mtDNA disorders. The report concluded no overall ethical objection to the use of these technologies in humans for treatment of mtDNA disease, although further investigation is needed to confirm the safety of the techniques. They also recommend that patients are provided with appropriate information and support before and throughout the treatment. Suitably trained and updated individuals should deliver information to prospective patients.

To broaden our knowledge and monitor the outcome of these therapies, the Nuffield Council also advises follow-up and assessment of the resulting children. In terms of regulation, other recommendations also stipulate that the status of mitochondrial donors should differ from oocyte or embryo donors and their identity need not necessarily be disclosed to the children once they reach adulthood.[22] This could potentially be a positive feature of this type of donation and result in more women being willing to donate their oocytes for these treatments, as the legalities of gamete donation can discourage some

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persons from donating. In 2014 the UK government proposed change in legislation to grant mitochondrial donors anonymity.[23] The Food and Drug Administration (FDA) of the USA, in February 2014, discussed drafting guidelines for the design of clinical trials, but has not published the final document. It was acknowledged that clinical research would also be needed for validation of mitochondrial replacement to treat female infertility. The committee agreed on inclusion criteria for participants and the use of ‘historical controls’.

Manufacturing controls and quality assessment of techniques, and how these factors could contribute to risk reduction for the participants and their future children, were also discussed. The FDA Cellular, Tissue and Gene Therapies Advisory Committee concluded that currently there is a lack of animal data to commence human clinical trials. Some members suggested additional research in alternative animal species concurrently as no single model emulates human physiology. Aspects to be considered in these studies to supplement current data include: • Sufficient subject numbers • Evaluation from embryonic to postnatal stages • Follow-up (including analysis of neurologic, cardiopulmonary and motor function) • Assessment of the redox state • Mitochondrial carryover • Adverse nuclear-mitochondria interaction.

Other concerns raised included risks to the fetus and resulting children, many of which mirrored those in the UK report. Additionally, the committee reviewed the ethics of participation of these future children in clinical trials without informed consent. The FDA recommends setting up ‘centres of excellence’ in order to achieve standardisation of mitochondrial manipulation methods.[24] Undoubtedly, mitochondrial replacement therapy has a worthy place in assisted reproduction in the near future, as its benefit outweighs the associated ethical issues. Safety and efficacy must be optimised before human use but there is hope for families that want to prevent transmission of a mitochondrial disorder to their offspring.

When developing a new medical therapy one needs to consider first and foremost alleviation of suffering to the patients and their families.

Genetic manipulation in South Africa The South African National Health Act 61 of 2003 (NHA), Chapter 8: ‘Control of use of Blood, Blood Products, Tissue and Gametes in Humans’ [25] states: ‘A person may not – (a) manipulate any genetic material, including genetic material of human gametes, zygotes or embryo; or (b) engage in any activity, including nuclear transfer or embryo splitting, for the purpose of the reproductive cloning of a human being.’

The document further defines ‘reproductive cloning of a human being’ as: ‘the manipulation of genetic material in order to achieve the reproduction of a human being and includes nuclear transfer or embryo splitting for such purpose’.

The NHA does not mention alteration of germ line genetics or reproductive embryo cloning. Transfer of mtDNA even in the form of blastomere nuclei (the technique which has been scrutinised the

PLURIPOTENT STEM CELLS most by ethicists) is not ‘reproductive cloning of a human being’. The document also does not specify that genetic material may not be manipulated for any other reasons. Does this mean that one could undertake mitochondrial transfer in the realms of the South African legal context? It is likely that ministerial authorisation will be required.

Concluding remarks and perspectives Both the social and scientific aspects of a new healthcare technology must be considered. Regarding social and moral principles, many believe that some ART techniques go beyond the border of acceptable medical intervention. It is reasonable that these opinions should be considered, but who decides on what is globally acceptable and what is not? Diverse social, ethical, religious, cultural, political, scientific and clinical bodies will have differing attitudes. Public opinion can also make a difference today, more than it could in the past. However, is the public aware of techniques that have been in place for decades in assisted reproduction technology, without appropriate evidence-based data being gathered before implementation? The introduction of novel germ line therapies into humans has proved how important it is for the gap between scientific fact and public opinion to be overcome. The Nuffield Council on Bioethics has achieved this through a comprehensive review of the issues surrounding prevention of mtDNA disease by examining the techniques from many angles. The report also highlighted how some features of the therapies do not truly deviate from what is already considered socially acceptable.[22] However, once mitochondrial transfer becomes available to patients, long-term follow-up monitoring of the resultant children born by these techniques must be performed.

The UK Department of Health has published draft regulations for new techniques to prevent the transmission of mitochondrial disease.[26] These regulations suggest creation of a national or worldwide database that can easily be accessed to encourage information sharing of patient data and improvement and optimisation of the techniques. The UK parliament has debated mitochondrial transfer since 2012[27,28] and in February 2015 finally voted in favour of human mitochondrial replacement legalisation to allow the commencement of human clinical application. These Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 will apply from 29 October 2015.[29] With regard to South African legislation,[25] alteration of germ line genetics and cloning other than reproducing human beings is not mentioned, and it is not clear whether the lack of information on these techniques implies that they are not prohibited.

Funding. This research and the publication thereof is the result of funding provided by the Medical Research Council of South Africa in terms of the MRC’s Flagships Awards Project SAMRC-RFA-UFSP-01-2013/ STEM CELLS.

References 1. Giles RE, Blanc H, Cann HM, Wallace DC. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A 1980;77(11):6715-6719. [http:// dx.doi.org/10.1073/pnas.77.11.6715] 2. Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF. Treatment for mitochondrial disorders. Cochrane Database Syst Rev 2012;4:CD004426. [http:// dx.doi.org/10.1002/14651858.cd004426.pub3] 3. DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003; 348(26):2656-2668. [http://dx.doi.org/10.1056/nejmra022567] 4. Schapira AHV. Mitochondrial disease. Lancet 2006;368(9529):70-82. [http:// dx.doi.org/10.1016/s0140-6736(06)68970-8] 5. Tachibana M, Sparman M, Sritanaudomchai H, et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009;461(7262):367-372. [http://dx.doi.org/10.1038/nature08368]

6. Cohen J, Scott R, Alikani M, et al. Ooplasmic transfer in mature human oocytes.

Mol Hum Reprod 1998;4(3):269-280. [http://dx.doi.org/10.1093/molehr/4.3.269] 7. Barritt J, Willadsen S, Brenner C, Cohen J. Cytoplasmic transfer in assisted reproduction. Hum Reprod Update 2001;7(4):428-435. [http://dx.doi. org/10.1093/humupd/7.4.428] 8. Craven L, Tuppen HA, Greggains GD, et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 2010;465(7294):8285. [http://dx.doi.org/10.1038/nature08958] 9. Roberts RM. Prevention of human mitochondrial (mtDNA) disease by nucleus transplantation into an enucleated donor oocyte. Am J Med Genet 1999;87(3): 265-266. [http://dx.doi.org/10.1002/(sici)1096-8628(19991126)87:3%3C265::aidajmg14%3E3.0.co;2-s] 10. Craven L, Elson JL, Irving L, et al. Mitochondrial DNA disease: New options for prevention.

Hum Mol Genet 2011;20(R2):R168-174. [http://dx.doi.org/10.1093/hmg/ddr373] 11. Tachibana M, Sparman M, Mitalipov S. Chromosome transfer in mature oocytes.

Fertil Steril 2012;97(5):e16. [http://dx.doi.org/10.1038/nprot.2010.75] 12. Tachibana M, Amato P, Sparman M, et al. Towards germline gene therapy of inherited mitochondrial diseases. Nature 2013;493(7434):627-631. [http://dx.doi. org/10.1038/nature11647] 13. Barritt JA, Brenner CA, Malter HE, Cohen J. Mitochondria in human offspring derived from ooplasmic transplantation. Hum Reprod 2001;16(3):513–516. [http://dx.doi.org/10.1093/humrep/16.3.513] 14. Krimsky S. Is ooplasm transfer safe for the offspring? Adapted from testimony submitted to the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee.

GeneWatch 2014;27(3):22-23.

15. Bredenoord AL, Pennings G, de Wert G. Ooplasmic and nuclear transfer to prevent mitochondrial DNA disorders: Conceptual and normative issues. Hum Reprod Update 2008;14(6):669-678. [http://dx.doi.org/10.1093/humupd/dmn035] 16. Isasi RM, Knoppers BM. National regulatory frameworks regarding human cloning for reproductive and therapeutic/research purposes: A report for the genetics and public policy center, 2006. http://www.dnapolicy.org/pdf/cloning. pdf (accessed 22 January 2015).

17. Bredenoord AL, Dondorp W, Pennings G, De Wert G. Nuclear transfer to prevent mitochondrial DNA disorders: Revisiting the debate on reproductive cloning. Reprod Biomed Online 2011;22(2):200-207. [http://dx.doi.org/10.1016/j.rbmo.2010.10.016] 18. Briscoe R. Ethical considerations, safety precautions and parenthood in legalising mitochondrial donation. New Bioeth 2013;19(1):2-17. [http://dx.doi.org/10.1179 /2050287713z.00000000027] 19. Monk C, Spicer J, Champagne FA. Linking prenatal maternal adversity to developmental outcomes in infants: The role of epigenetic pathways. Dev Psychopathol 2012;24(4):1361-1376. [http://dx.doi.org/10.1017/s0954579412000764] 20. Golombok S. Presentation to the Nuffield Council’s Working Group: Fact-finding meeting. Centre for Family Research, University of Cambridge, 2012.

21. Blake L, Casey P, Readings J, Jadva V, Golombok S. ‘Daddy ran out of tadpoles’: how parents tell their children that they are donor conceived, and what their 7-year-olds understand. Hum Reprod 2010;25(10):2527-2534. [http://dx.doi. org/10.1093/humrep/deq208] 22. Nuffield Council on Bioethics. Report – Novel Techniques for the prevention of mitochondrial DNA disorders: An ethical review. London: Nuffield Council of Bioethics, 2012:52-90.

23. Macrae F. Third parent in IVF cases will not be named: Britain to allow triple-donor embryos to halt genetic diseases in world first - but extra mother’s identity will be kept secret. Daily Mail Online News, 2014. http://www.dailymail.co.uk/news/article-2877667/ UK-proposes-rules-embryos-3-people.html (accessed 23 January 2015).

24. Food and Drug Administration. Cellular Tissue and Gene Therapies Advisory committee; Meeting minutes. United States of America 2014. http://www.fda.gov/ AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/ CellularTissueandGeneTherapiesAdvisoryCommittee/ucm380047.htm (accessed 25 January 2015).

25. Republic of South Africa. National Health Act 61. Pretoria: Government Gazette 2003. http://www.acts.co.za/national-health-act-2003/ (accessed 23 January 2015).

26. United Kingdom. Department of Health. https://www.gov.uk/government/ uploads/system/uploads/attachment_data/file/285251/mitochondrial_donation_ consultation_document_24_02_14_Accessible_V0.4.pdf. (accessed 26 January 2015).

27. Barber S, Border P. United Kingdom Parliament. Mitochondrial donation.

Standard Note: SN/SC/6833. London: House of Commons Library. 2015. http:// www.parliament.uk/business/publications/research/briefing-papers/SN06833/ mitochondrial-donation (accessed 23 January 2015).

28. Human Fertilisation and Embryology Authority. Mitochondrial donation: An introductory briefing note: October 2014. London: Human Fertilisation and Embryology Authority, 2014. http://www.hfea.gov.uk/docs/2014-10-01_Mitochondrial_ donation__an_introductory_briefing_note_-_final.pdf (accessed 23 January 2015).

29. The Stationery Office Limited. Statuary Instruments 2015 No. 572: Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015.

London: The Stationery Office Limited, 2015. http://www.legislation.gov.uk/ uksi/2015/572/pdfs/uksi_20150572_en.pdf (accessed 20 May 2015).

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STEM CELL TOURISM

Legal implications of translational promises of unproven stem cell therapy W M Botes,1 B Proc, LLB, LLM; M Alessandrini,2 PhD Dyason Inc, 134 Muckleneuk St, Nieuw Muckleneuk, Pretoria, South Africa Department of Immunology, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine, South African Medical Research Council Extramural Unit for Stem Cell Research and Therapy, University of Pretoria, South Africa 1 2

Corresponding author: W M Botes (marietjie@dyason.co.za)

The promise stem cell therapy holds for curing diseases for which no therapy currently exists is often translated as fact. Unfortunately, enforced misconceptions between fact and promise often also translate into exploitation and harming of patients. This article aims to clear up misconceptions about the biological promise and legal consequences of insisting on promises not based on scientific facts.

S Afr J BL 2015:8(2 Suppl 1):36-40. DOI:7196/SAJBL.8005

Stem cells hold great promise for treating and potentially curing many diseases for which no therapy currently exists. However, several misconceptions of stem cells exist among the general public and, to an extent, among the medical fraternity. Most of these misconceptions can be resolved by understanding the basic biology of stem cells, which would be critical to address prior to arguing the associated ethical and legal implications that arise from the use of stem cells for therapeutic purposes.

A stem cell has the unique ability to both replicate and develop into specialised tissues with specific functions. Different forms of stem cells exist, each with varying capacity or potency. The potency refers to the extent to which the stem cell is able to replicate and differentiate into multiple tissues. When the female egg cell is fertilised by the male sperm, a totipotent stem cell is created, from which a complete human body and placenta develops. On the fourth day of development, the embryo forms an outer layer of cells and an inner cell mass. The outer layer develops into the placenta, while the inner cell mass develops into the human body/fetus. Embryonic stem cells (ESCs) are derived from the inner cell mass and are referred to as pluripotent stem cells. Somatic stem cells (often referred to as adult stem cells) are stem cells that reside in tissues and organs of the developed human body for the purpose of providing a renewal and regenerative capacity. This capacity is generally limited to the tissue-group within which these stem cells reside. These stem cells are referred to as multipotent stem cells. Best known examples of multipotent stem cells are haematopoietic stem cells (HSCs), which give rise to all of the cellular components of blood; mesenchymal stem cells (MSCs), which are able to develop into bone, cartilage, muscle and fat; and neural stem cells (NSCs), which develop into cells of the nervous system.

From a therapeutic point of view, HSCs are the only form of globally accepted stem cell therapy. These cells are used for the treatment of blood and blood-related disorders, and are common practice in nearly 80 countries. This is a well-described and rational approach where ‘blood-making’ stem cells are used specifically in the context

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of replacing defective blood cells. Of the more than 60 000 HSC transplants that take place globally per annum, approximately 90% are for treating blood cancers (leukaemia, lymphoma and myeloma), while the remaining indications include solid tumours and nonmalignant conditions such as thalassaemia, sickle cell disease and immune disorders. In each of these cases, the HSCs are used to replenish blood cells that are depleted in a chemotherapy regimen received prior to the transplantation.

Over the past decade, the potential benefits of MSCs for treatment purposes have gained tremendous interest. There are several reasons for this, including the fact that these cells: • Can be procured fairly easily (particularly from fat) • Have the unique ability to migrate to the site of injury once injected • Do not require genetic matching when obtained from a donor (as is the case with HSCs).

By investigating the global clinical trial landscape of MSCs, it was possible to identify over 100 different indications that have been or are currently being treated with MSCs (manuscript in preparation). These include diseases such as arthritis, heart attacks, multiple sclerosis, diabetes and spinal cord injuries. However, although widespread interest in this area of research exists, only one MSC product has successfully achieved market approval from regulatory authorities – remestencel-L (Prochymal®), which was approved in Canada and New Zealand for the treatment of graft v. host disease, a complication of HSC transplantation.[1] The stem cell controversies of the past two decades originated from the use of ESCs for medical research. Given that a fertilised embryo is destroyed in order derive these cells, albeit in the laboratory setting with donated embryos, such research was deemed unacceptable by many and understandably has resulted in a quagmire of ethical debates.[2] More recently, however, the use of unproven stem cell therapies and the subsequent emergence of a ‘stem cell tourism’ industry have provided a concerning source of controversy.[3] In such cases, vulnerable patients are enticed to travel abroad to dubious stem cell clinics and are subjected to unproven stem cell therapies at

STEM CELL TOURISM their own expense. Given the unique properties of MSCs and the ease with which they can be prepared from fat tissue, they have become the most attractive product on offer at a large number of suspicious stem cell clinics around the world. The most concerning aspect of this is the extensive list of diseases that these clinics claim to treat.

Although over 100 indications are being treated in the clinical trial setting, none have been able to demonstrate sufficient benefit (with the exception of the previously mentioned Prochymal® preparation).

In December 2014, the Food and Drug Administration (FDA) – the American regulatory authority – released two draft guidance documents, describing their view on the preparation of MSCs from fat and their use in patients. In essence, these draft guidelines state that MSCs are to be regarded as biological drugs in future, meaning that the provider and/or manufacturer will have to prove benefit in the clinical trial setting before it will be reviewed and considered for marketing approval by the FDA. Once this becomes official, no clinic in the USA will be able to offer unproven MSC products legally. Since there is no approved MSC therapy in the US market, any clinic preparing MSCs for treatment purposes will stand the risk of having to engage legally with the FDA, for which the outcome will in all likelihood be in favour of the latter. It is anticipated that regulatory authorities in other major markets will follow suit, particularly the European Union.

Stem cell therapy as biological medicine In South Africa (SA) MSC therapy is similarly categorised as a biological medicine in terms of the Medicine Control Council’s (MCC). Guidelines for the Registration of Medicines where the active ingredient or key excipients have been derived from living organisms or tissues, or manufactured using a biological process.[4] Biological medicines are therefore largely differentiated from other medicines through the methods used to manufacture them and include ‘medicines prepared from substrates such as: (1) microbial cultures (fermentation); (2) plant or animal cell cultures (including those resulting from recombinant DNA or hybridoma techniques); (3) extraction from biological tissues; and (4) propagation of live agents in embryos or animals.’[5] Considering its production methods stem cell therapy qualifies as biological medicine and falls within the ambit of the Medicines and Related Substances Control Act (MRSCA).[6] The classification of stem cell therapy as biological medicine with regard to autologous stem cell therapy, where a patient’s own stem cells are administered back to the same patient after having been processed, cultured, mixed with other therapeutic substances, stored or even cryopreserved, was challenged in the USA in the Regenexxcase.[7] In this case the FDA claimed that the autologous stem cell based substance produced using the Regenexx procedure qualifies as a ‘biological product’ that falls within the regulatory ambit of the FDA and subsequently ordered its developers, Regenerative Sciences, to stop offering their unapproved biological drug product. However, foreign to SA regulations, the FDA regulations mandate the FDA to only regulate so-called ‘one-on-many’ public health risks as opposed to ‘one-on-one’ doctor-patient medical care risks. The developers of Regenexx argued that their product, based on its ‘one-on-one’ doctor-patient medical care risk, did not fall under the regulation of the FDA and accordingly did not require any approval from the FDA. The important fact is that the court found that ‘the biological characteristics of the cells changed during the process’ causing the cells to be more than ‘minimally manipulated’ resulting in a biological medicinal product. In SA, autologous stem cell products similar to

Regenexx also qualify as biological medicine, as described above and will be regulated by the MRSCA.[5]

Registration of biological medicine The MRSCA prohibits the sale of any unregistered medicine which is subject to registration.[8] An official notice issued in terms of the MRSCA by the MCC specifically subjects all medicines that are biological medicine to registration with the MCC.[9] Only when the Registrar of Medicines is satisfied that medicine is safe, efficacious, of good quality and suitable for the purpose for which it is intended, complies with the prescribed requirements and that registration thereof is in the public interest will he or she approve an application for registration and issue the applicant with a certificate of registration, which after the registered medicine can be legally sold.[10] Biological medicine will also be evaluated for safety, quality and efficacy by the Biological Medicines Committee prior to registration, in addition to the standard MCC committees.[11] In this regard the MCC will consider both national and international guidelines such as the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, which focuses on global harmonisation of safety, efficacy and quality standards resulting from Good Manufacturing Practices and properly designed and conducted clinical trials.[12] Although selling unregistered medicine is an offence punishable with a fine and/or imprisonment not exceeding 10 years, prosecutions and convictions are extremely rare.[13]

Consequences of unproven or fraudulent stem cell therapy It has been recorded that money spent on stem cell tourism, including clinically unproven treatments, averages around R122 500, and that some stem cell tourists even received stem cells from animals such as sheep or rabbits.[14] From 2002 to 2006 Biomark International, a biotechnology company in the USA, defrauded individuals suffering from amyotrophic lateral sclerosis (Lou Gehrig’s disease), Parkinson’s disease, muscular dystrophy, multiple sclerosis and other incurable diseases by making false representations ‘...that science had proven the therapeutic power of stem cells and that Biomark was simply making it available to the world.’[15] Under these pretences every patient was injected with the same type and quantity of stem cells, regardless of the disease the patient was suffering from and charged between US$10 000 and US$32 000, if not negotiated otherwise.

In 2006 Laura Brown and Stephen Mark van Rooyen, directors of Biomark, were criminally indicted. During their hearing the court found that Biomark’s website and advertisements made numerous false, misleading and inaccurate statements and that the proffered information had no scientific credibility. It further found that the stem cell treatments were illegally administered without a biologics product licence[16] and that licensing was very unlikely as pre-clinical trials in this regard only involved non-humans. None of the patients undergoing these treatments were cured and many even died during treatment.

Undesirable practices Joint efforts of stem cell researchers, clinicians, ethicists and regulatory officials from 13 countries culminated in the International Society for Stem Cell Research’s (ISSCR) Guidelines for the Clinical Translation of Stem Cells.[17] These guidelines acknowledge the worrisome

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STEM CELL TOURISM cases where unproven stem cell therapies are marketed, resulting in stem cell tourism to countries with insufficient local regulation and oversight of host clinics. It also condemns the administration of unproven stem cell therapy or direct derivatives to patients outside of a clinical trial, especially when charged for such services. It states that countries hosting illegal therapies have a responsibility to prevent patient exploitation and urges them to close fraudulent clinics and take disciplinary action against involved clinics.

Locally, authorised institutions[18] may acquire, use and supply any blood products, including stem cells, for prescribed medical purposes, the advancement of health and therapeutic services and the production of therapeutic, diagnostic or prophylactic substances.[19] These activities are largely controlled by the Minister of Health as only he has the authority to authorise cell removal and impose conditions.[20] This process may significantly frustrate or delay translational stem cell research. Regulations, issued in terms of the National Health Act (NHA) which only requires informed consent from the stem cell donor when acquiring cells, contradicts this prescription, leaving legal uncertainty in its wake.[21] The MRSCA requires that the Director-General of Health must be informed of the therapeutic efficacy and effect of any medicine as soon as practically possible after registration with the MCC, including the purpose, circumstances and manner in which such medicine should be used.[22] Any advertisements subsequent to such registration, making any claims regarding the therapeutic effects and efficacy of the medicine or use thereof for any purposes contrary to the reported effects, efficacy and purpose of use is prohibited as being false or misleading.[23] All transactions or agreements concluded between healthcare providers and patients for the supply of healthcare goods, including biological medicine, or services in exchange for consideration, including the marketing of stem cell therapies, falls within the ambit of the Consumer Protection Act (CPA).[24] The CPA also prohibits false or misleading marketing which includes deceptions of the nature, properties, advantages or uses of goods or services, the conditions under which and the prices at which goods or services can be supplied or any other material aspect.[25] Patients may therefore not be enticed into stem cell therapy with scientifically unproven promises or false statements relating to the exact nature and possible effects of such therapy. Patients suffering from debilitating diseases are often physically and mentally handicapped as a result and unable to substantially protect their own interests. Should physical force, coercion, undue influence, pressure, duress, harassment or unfair tactics be used against these patients when marketing, supplying or negotiating the supply of any stem cell therapy, such conduct will amount to being unconscionable in terms of the CPA.[26] Practices where suppliers of stem cell therapy knowingly take advantage of illiterate, ignorant patients who are unable to understand the language of the agreement are prohibited by the CPA. Failing to correct patients’ apparent misapprehension of proposed stem cell therapy, using exaggeration, innuendo or ambiguity as to material facts or failing to disclose material facts relating to stem cell therapy will also amount to a false, misleading or deceptive representation.[27] Any agreement between patients and suppliers of stem cell therapies which subjects patients to any of the aforementioned fraudulent conduct, contravenes any of the provisions of the CPA or constitutes an assumption of risk or liability

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by the patient for losses suffered resulting from the gross negligence of suppliers or any persons acting for or on behalf of suppliers is strictly prohibited.[28] The agreed price for the therapy as well as the manner in which the therapy will be administered must also be fair, reasonable, just and may not waive any liability of suppliers or rights of patients.[29] Liability resulting from stem cell therapy can accordingly not be escaped through contractual terms.

Any contravention of the aforementioned provisions, which may result in serious illness, disablement or even death of the patient, is considered to be serious enough that patients may deviate from the standard consumer complaint route and directly approach the court to restore money to the patient or compensate the patient for losses or expenses relating to harm suffered resulting from stem cell therapy transactions or agreements, including the patient’s legal costs relating to such court proceedings.[30] Although the CPA does not limit the heads of damages that may be claimed upon contravention of these prohibitions, it is arguable that the patient will also be entitled to claim for general damages. The court will, among others, consider the power imbalances between the parties which is influenced by the parties’ relationship to each other, their relative capacity to enter into contractual agreements, levels of education and sophistication, experience and bargaining position; whether the patient knew or ought reasonably to have known of the existence and extent of any unfair, unreasonable or unjust provisions contained in the agreement; the respective conduct of suppliers and patients; the amount for which, and circumstances under which the patient could have acquired identical or equivalent goods or services from a different supplier and whether the biological medicine was manufactured, processed or adapted to special orders of the patient.[31] The court can also require the supplier to cease any stem cell therapy or alter any practices to avoid a repetition of the supplier’s conduct in an effort to prevent further future harm to patients.[32] If the MCC is also of the opinion that it is not in the public interests that any medicine be made available to the public it may order the disposal of any undesirable medicine.[33] The premature translation of unproven stem cell therapy resulting in such court and disposal orders can destroy people’s trust in stem cell therapy and negatively impact on current translational research, future funding and development of this promising biological medicine.

Patient safety Although false and misleading advertising is punishable as a criminal offence in terms of the MRSCA,[34] these practices can also result in civil liability in terms of the implied warranty[35] and faultless liability regimen[36] provided for in the CPA. The CPA provides for the joint and individual liability of all persons involved in the chain supplying any unsafe, hazardous goods without adequate instructions or warnings pertaining to any hazard that can result from using such goods ‘...irrespective of whether the harm resulted from any negligence...’[37] on the suppliers’ part. A patient only needs to prove that the harm (death, injury, illness or pure economic loss) he wrongfully suffered resulted from unsafe or hazardous stem cell therapy, without adequate instructions or warnings pertaining to such hazards, to succeed with his claim against any person in the therapy’s supply chain.

Patients are entitled to assume that suppliers of stem cell therapies have the legal right to sell and administer biological medicine.[38] This presumption entails that a patient has the right to assume that any biological medicine offered as therapy has been registered with the MCC

STEM CELL TOURISM subsequent to clinical studies providing evidence of product safety and established proof-of-principle for the desired therapeutic effect,[39] failing which, and upon suffering harm as a result of unproven, unregistered therapy, a patient can claim for damages as discussed above.

Every patient has the right to information regarding proposed stem cell therapy in plain understandable language so that a person of average literacy skills and minimal experience as a consumer of biological medicine, could be expected to understand the content and significance of such information.[40] Considering the novelty of stem cell treatments almost everyone will be considered to have minimal experience with such therapy and with further regard to the complex and unpredictable nature thereof, healthcare practitioners will need to take extraordinary communication steps to ensure that patients adequately understand and consent to such therapies. Information relating to genetically modified ingredients or reconditioned goods, as may be the case with stem cell products, must be clearly displayed on the biological medicine’s packaging or prescribed notice.[41] This, as well as the extensive guidelines offered by the ISSCR[17] will further aid patients in exercising informed decisions regarding their treatment options.

Patients can further expect goods or services to be safe, free of defects or hazard,[35,42] such as contamination, and of a quality that persons are generally entitled to expect from stem cell therapy.[43] Having regard to the novelty, unpredictability and unknown long-term results of stem cell therapy it is questionable what exactly persons are generally entitled to expect of it. What is clear is that unproven stem cell therapies, posing significant risks of personal injury, qualify as unsafe and hazardous in terms of the CPA, and patients are entitled to be protected from such dangers.

Whenever the stipulations of any other act is in conflict with those contained in the CPA, the act offering the greater protection to the consumer, being the patient, will apply.[44]

Medical innovation Stem cell based medical innovation interventions are unproven stem cell based interventions outside the context of a formal clinical trial.

In very limited cases the ISSCR guidelines allow clinicians to attempt medically innovative stem cell based interventions on seriously ill patients, albeit under heightened levels of caution and with informed consent clearly emphasising the experimental and preliminary nature of the clinical intervention.[45] A case in point is the stem cell therapy received by Gordon Howie, a Canadian ice hockey player, after suffering a stroke in October 2014.[46] However, due to the fact that patients do not receive these treatments for consideration, these transactions will locally not fall within the ambit of the CPA and patients will no longer enjoy the faultless liability the protection affords. However the principles of therapeutic research in SA include well-informed consent and the constitutional protection of research participants’ bodily and psychological integrity,[47] ethically reviewed research proposals to ensure safety monitoring and the management of any harm experienced by participants, including compensation for any researchrelated injuries and providing for the long-term care and observation of participants of innovative therapy such as stem cell therapy.[48]

Conclusion In countries which are unregulated or poorly regulated, undesirable practices, inviting stem cell tourists and patient harm resulting from unproven stem cell therapy, would thrive as patients will increasingly

move into areas that are medically untested. In SA the MRSCA, regulating the quality of biological medicine which enters the market through registration, and the CPA, providing patients with remedies when suffering harm or losses resulting from stem cell therapies, protects patients against undesirable practice and its inherent dangers to patient safety.

Funding. This research and the publication thereof is the result of funding provided by the Medical Research Council of South Africa in terms of the MRC’s Flagships Awards Project SAMRC-RFA-UFSP-01-2013/ STEM CELLS.

References 1. Mesoblast: The Regenerative Medicine Company. ASX Announcement: Mesoblast provides updates on clinical programs of Prochymal® for Crohn’s disease and acute graft-versus-host disease. 29 April 2014. http://globenewswire.com/newsrelease/2014/04/29/630744/10078747/en/Mesoblast-Provides-Update-onClinical-Programs-of-Prochymal-for-Crohn-s-Disease-and-Acute-Graft-VersusHost-Disease.html (accessed 16 February 2015) 2. King NMP, Perrin J. Ethical issues in stem cell research and therapy. Stem Cell Res Ther 2014; 5(4):85. [http://dx.doi.org/10.1186/scrt474] 3. Meissner-Roloff M, Pepper MS. Curbing stem cell tourism in South Africa. Applied & Translational Genomics 2003;2:22-27.

4. Medicines Control Council. Guidelines for the Registration of Medicines: General Information, 2012, Version 8. http://www.kznhealth.gov.za/research/mccinfo.pdf (accessed 16 February 2015).

5. Mahomed S, Nöthling Slabbert M. Stem cell tourism in South Africa: The legal position. S Afr J BL 2012;5(2):69-73. [http://dx.doi.org/10.7196/sajbl.235] 6. Republic of South Africa. Medicines and Related Substances Act 101. Government Gazette 1965.

7. Jordaan D. Regulatory crackdown on stem cell therapy: What would the position be in South Africa? S Afr Med J 2012;102(4):219-220.

8. Republic of South Africa. Medicines and Related Substances Act, Section 14(1).

Government Gazette 1965.

9. Republic of South Africa. Medicine and Related Substances Act, Notice in terms of section 14(2), published in Government Notice R510 in Government Gazette 24727 (as amended) commencing on 2 May 2003.

10. Republic of South Africa. Medicine and Related Substances Act 101, Section 15.

Government Gazette 1965.

11. Medicine Control Council. Guidelines for the Registration of Medicines: General Information. 2012. Version 8. http://www.kznhealth.gov.za/research/mccinfo.pdf (accessed 16 February 2015).

12. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. http://www.ich.org/products/ guidelines.html (accessed 16 February 2015).

13. Republic of South Africa. Medical and Related Substances Act 101, Section 29.

Government Gazette 1965.

14. Pepper MS. The stem cell regulatory environment in South Africa – causes for concern. S Afr Med J 2009;99(7):736-737. [http://dx.doi.org/10.7196/SAMJ.5940] 15. United States of America v. Laura Brown and Stephen Mark van Rooyen decided on 28 March 2006 in the United States District Court for the Northern District of Georgia, Atlanta Division under case number 1:06-cr-00153-UNA, Criminal Indictment No: 1:06CR153 16. United States of America. Public Health Services Act , Title 42 United States Code, Section 262(a)(1) 17. International Society for Stem Cell Research (ISSCR). Guidelines for the Clinical Translation of Stem Cells. 3 December 2008. http://www.isscr.org/clinical_trans/ pdfs/ISSCRGLClinicalTrans.pdf (accessed 21 February 2015).

18. Republic of South Africa. National Health Act 61, Section 90. Government Gazette 2003.

19. Republic of South Africa. Sections 56(1) and 64, National Health Act and Regulations relating to Stem Cell Banks and the General Control of Human Bodies, Tissue, Blood and Blood Products and Gametes issued in terms of Section 68. Government Gazette 2003.

20. Republic of South Africa. National Health Act, Sections 56(2)(a)(iv), 54(3), 57(2) and (4). Government Gazette 2003.

21. Republic of South Africa. Regulations relating to the Use of Human Biological Material issued in terms of Section 68, National Health Act. Government Gazette 2003.

22. Republic of South Africa. Medical and Related Substances Act 101, Section 22(1) (a). Government Gazette 1965.

23. Republic of South Africa. Medical and Related Substances Act 101, Section 20(1).

Government Gazette 1965.

24. Nöthling Slabbert M, Maister B, Botes M, Pepper MS. The application of the Consumer Protection Act in the health care context: Concerns and Recommendations. Compar Int Law J S Afr 2011;44(2):168-203.

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STEM CELL TOURISM 25. Republic of South Africa. Consumer Protection Act 68, Section 29. Government Gazette 2008.

26. Republic of South Africa. Consumer Protection Act 68, Section 40. Government Gazette 2008.

27. Republic of South Africa. Consumer Protection Act 68, Section 41. Government Gazette 2008.

28. Republic of South Africa. Consumer Protection Act 68, Section 51. Government Gazette 2008.

29. Republic of South Africa. Consumer Protection Act 68, Section 48. Government Gazette 2008.

30. Republic of South Africa. Consumer Protection Act 68, Section 52(3). Government Gazette 2008.

31. Republic of South Africa. Consumer Protection Act, Section 52(2). Government Gazette 2008.

32. Republic of South Africa. Consumer Protection Act, Section 52(3)(b)(iii).

Government Gazette 2008.

33. Republic of South Africa. Medicines and Related Substances Act 101, Section 23.

Government Gazette 1965.

34. Republic of South Africa. Medicines and Related Substances Act 101, Section 29.

Government Gazette 1965.

35. Republic of South Africa. Consumer Protection Act 68, Sections 55 and 56(1).

Government Gazette 2008.

36. Republic of South Africa. Consumer Protection Act 68, Section 61. Government Gazette 2008.

37. Republic of South Africa. Consumer Protection Act 68, Section 61(1). Government Gazette 2008.

38. Republic of South Africa. Consumer Protection Act 68, Section 44(1)(a).

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Government Gazette 2008.

39. ISSCR. Recommendations 11-26. Guidelines for the Clinical Translation of Stem Cells. 3 December 2008. http://www.isscr.org/clinical_trans/pdfs/ ISSCRGLClinicalTrans.pdf (accessed 21 February 2015) 40. Republic of South Africa. Consumer Protection Act 68, Section 22. Government Gazette 2008.

41. Republic of South Africa. Consumer Protection Act 68, Sections 24(6) and 25(1).

Government Gazette 2008.

42. Republic of South Africa. Consumer Protection Act 68, Sections 54(1)(c) and 55.

Government Gazette 2008.

43. Republic of South Africa. Consumer Protection Act 68, Section 53. Government Gazette 2008.

44. Republic of South Africa. Consumer Protection Act 68, Section 2(9)(b).

Government Gazette 2008.

45. ISSCR. Recommendation 27-34. ISSCR. Guidelines for the Clinical Translation of Stem Cells. 3 December 2008. http://www.isscr.org/clinical_trans/pdfs/ ISSCRGLClinicalTrans.pdf (accessed 21 February 2015) 46. Halford M. Gordon Howie makes ‘amazing’ recovery following stem cell treatment in Mexico. NBC Sports: Pro Hockey Talk. 19 December 2014. http:// prohockeytalk.nbcsports.com/2014/12/19/gordie-howe-makes-amazingrecovery-following-stem-cell-treatment-in-mexico/ (accessed 22 February 2015).

47. Republic of South Africa. Constitution of the Republic of South Africa 108. Section 12, Chapter 2: Bill of Human Rights. Government Gazette 1996.

48. Republic of South Africa. Regulations relating to Research on Human Subjects (Gazettes 36508, Regulation 378) issued in terms of Section 68, National Health Act 61.

Government Gazette 2003.

STEM CELL TOURISM

Stem cell tourism in South Africa: A legal update M Nöthling Slabbert,1 BA, BA Hons, MA, DLitt, LLB, LLD; M S Pepper,2 MB ChB, PhD, MD; S Mahomed,3 LLB, BCom, LLM, PhD candidate Department of Jurisprudence, School of Law, University of South Africa, South Africa Department of Immunology, Faculty of Health Sciences, Institute for Cellular and Molecular Medicine and MRC Extramural Unit for Stem Cell Research and Therapy, University of Pretoria, South Africa; Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Switzerland 3 Steve Biko Centre for Bioethics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 1 2

Corresponding author: M Nöthling Slabbert (slabbmn@unisa.ac.za)

The past few years have seen a sharp rise in the propagation of unproven stem cell ‘treatments’, also known as ‘stem cell tourism’. Patients suffering from a variety of diseases unresponsive to conventional medical therapy often travel to certain destinations to receive these therapies, mostly from bogus operators advertising various ‘stem cell treatment cures’ for a wide range of conditions, and in the process mislead vulnerable patients with unfounded promises of recovery. Stem cell tourism, made possible by legal lacunae or weak national regulatory frameworks, raises grave legal and ethical concerns, as patients not only receive treatments which are unproven, but often also unregulated, potentially dangerous and fraudulent. Existing proven therapeutic applications using stem cells are limited to those for blood and immunological disorders and are based on clinical trials that have demonstrated the efficacy and safety of these applications. As a result of weak legislative enforcement in this area, South Africa has unfortunately become an attractive destination for fraudulent stem cell operators.

The purpose of this article is provide an update on the South African legal position relating to stem cell therapy by evaluating the effectiveness of the Medicines and Related Substances Act and other relevant legislative provisions in regulating cell-based therapies, drawing strongly on recent international developments and case law in this field. The article will make specific recommendations aimed at improving the existing position.

S Afr J BL 2015;8(2 Suppl 1):41-45. DOI:10.7196/SAJBL.8006

Recent years have seen a sharp increase in the number of patients, with a variety of diseases unresponsive to conventional medicines, travelling to various juris­ dictions across the world to receive unproven stem-cell based treatments – a phenomenon pejoratively described as ‘stem cell tourism’.[1] This raises significant ethical concerns, as patients receive treatments that are unproven, often unregulated, potentially harmful, and often fraudulent.[2] Although stem cell therapy (defined as ‘the use of stem cells for therapeutic purposes’[3] is largely still experimental, proven existing therapeutic applications for stem cells (based on clinical trials that have demonstrated the efficacy and safety of these applications) are those used for the treatment of blood or immunological disorders, with bone marrow (BM) derived haematopoietic stem cells (HSCs) having been routinely used for more than 50 years.[4] Despite the existence of regulations governing research with human subjects, as well as medical malpractice and licensing laws in some jurisdictions, guidelines in general are not specific to stem cell therapy.[5] With increased attention following a number of adverse events resulting from some of these unfounded claims, the scientific community has begun to develop guidelines for researchers and physicians involved in the clinical translation of stem cell research. However, despite these efforts and international agreements aimed at addressing this gap,[6] not all accept or abide by these rules. The social media is used to advertise these ‘miracle’ cures as routine therapies and to entice ignorant and desperate patients.

The proliferation of these unproven ‘therapies’, no doubt facilitated by weak regulatory frameworks, also raises serious concerns about the exploitation of desperate and vulnerable patients, the regulation of cell-based therapies generally, as well as the governance of healthcare professionals.[7] It also jeopardises legitimate and inno­

vative translational stem cell research, emphasising the need for a clear distinction between reckless and unproven ‘therapies’ and legitimate, innovative stem cell-based interventions.

Late in 2012, a South African (SA) neurosurgeon, Dr Andre Liebenberg, claimed to have succeeded in paving the way for repairing spinal cord injuries using therapeutic stem cell cloning, by removing 35 mm from the spinal cord of a quadriplegic man and injecting a ‘special’ matrix containing these cells into the defect.[8] It subsequently emerged that, at that time, neither the neurosurgeon, nor his partner, Dr Gert Jordaan, had obtained prior ethical approval, subjected their work to peer review, published any of their research, or secured approval from the Medicines Control Council.[8] Their research has since been published.[9] Questioned at the time by the country’s stem cell experts, this example, conducted as an experimental treatment with the informed consent of the patient, was made possible by the legal lacunae that created opportunities for the development of unethical and unregulated practices in the stem cell field.[8] This example is relevant as it also illustrates the fine balance between scientific soundness in medical advancement, and uncontrolled experimental treatments that abuse patient vulnerability and compromise patient safety.

The SA population is particularly vulnerable in this regard, as limited information is available to provide South Africans with relevant, reliable and accurate information with regard to current, future or potential stem cell treatments.[4] In addition, physicians and healthcare providers are not informed of recent developments on a global front in this regard, nor of the legal implication in the South African context.[4] The purpose of this article is to provide an update on the SA legal position relating to stem cell therapy, by discussing relevant requirements contained in the Medicines and Related Substances Act and regulations,

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STEM CELL TOURISM as well as other relevant legislative provisions in regulating cell-based therapies, drawing strongly on recent international developments and case law in this field. The article concludes with recommendations aimed at improving the existing position.

Some ethical, legal and scientific issues relating to unproven stem cell treatments Safety, efficacy and quality

Unproven therapies generally fail to comply with relevant minimal ethical, scientific or medical standards of safety and efficacy which clinical trials set out to determine. An assessment of the balance between risks and benefits associated with the intervention is not undertaken, not to mention the absence of measures aimed at ensuring that patients (or participants) understand the key issues of the therapy, which includes a realistic description of prospective benefits, particularly in instances where an intervention has never been done before and patients’ hopes are high.

Unproven ‘treatments’ or ‘therapies’, mostly experimental in nature, are marketed as being successful based on unreliable and anecdotal evidence, including self-reports from patients.[2] Post-treatment care is seldom provided and there is no follow-up monitoring of patients or reporting of adverse events.[1] In addition, patients are charged excessive amounts for the therapy, which is a departure from the accepted norm that a provider of an experimental treatment does not charge a patient for the treatment.

Stem cell-based interventions are associated with medical risks, which may include tumour growth, immunological reactions, unexpected or unpredictable cell behaviour, as well as unknown long-term health consequences.[10] Producing and testing stem cells for quality in sufficient batches is another challenge. As transplanted stem cells remain in the bodies of patients for many years, side-effects and long-term safety should be determined.

Evidence of safety should be determined through appropriate preclinical studies in relevant animal models or through human studies involving similar cell-based interventions, with stricter requirements for safety where cells were manipulated ex vivo or were derived from induced pluripotent stem cells (iPSCs).[10] Medical trials involving experimental drugs may pose other complications, such as compensation claims for non-medical-related injuries, as was the focus of a recent landmark decision (the Roche[11] decision) in South Africa. Key principles of importance for this article emerging from the Roche judgment are that: • Regulators are responsible for assessing and approving the nature of the compensation for research-related injuries when reviewing and approving a study.

• Research participants are bound by the terms contained within the informed consent document approved by these regulators and any amendment thereto should be in writing and duly communicated to and noted by the regulator in order to be legally binding.

• An adequate informed consent process that distinguishes between researchers and sponsors and the limitation of compensation must be implemented.

• Delictual claims for research-related injuries will not succeed if a plaintiff has signed an informed consent document limiting his or her rights and which limits compensation.[11]

Ethical oversight and patient protection Unproven stem cell ‘treatments’ are often not part of clinical trials; no independent ethics review by recognised institutional review boards

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or ethics committees takes place and the research is not published in peer-reviewed journals, which makes replication of the research impossible.[1] Treatments are often offered in countries where it is difficult to institute medical negligence actions.[1] The National Health Act (NHA) stipulates that all health research which involves human participants requires an independent review by an accredited and registered research ethics committee.

Institutions conducting health research (e.g. private institutions and universities) must have an ethics committee or have access to one which is registered and accredited by the National Health Research Ethics Council.[12]The composition and operating procedures of ethics committees are described in the Act.[13] It is of utmost importance that because of possible unforeseen consequences and long-term health risks to participants or patients, ongoing regulatory oversight, once ethics approval has been granted, takes place.

Procedures to obtain voluntary informed consent from patients signing up for unproven therapies are often inadequate. Informed consent should strive to eliminate any possible misconceptions regarding therapeutic efficacy of the treatment, which is unlikely in the case of unproven treatments. The source of the stem cells should also be disclosed, for example cells derived from human fetuses or human embryonic stem cells (hESCs), which some patients may object to on moral grounds. In the case of some unproven treatments, a variety of cell sources are used, some even including animal tissue.[4] Where stem cell procedures are part of stem cell clinical trials, it is imperative that research ethics committees or institutional review boards consist of members with specific expertise in stem cell research and its clinical translation. Chapter 9 of the NHA sets out the requirements regarding research on or experimentation with human subjects, as well as those relating to health research ethics committees.

Patient autonomy It is trite that the ultimate decision to undergo or refuse a medical intervention is that of the patient and not the doctor.[14] This is also the case, if from the point of view of the medical profession, a patient’s refusal seems grossly unreasonable and might result in his or her death, and even if the medical practitioners involved take the view that disclosure of the risks and dangers in such circumstances is unnecessary or undesirable.[15] As far as the context of stem cell therapy is concerned, it should be noted that patient autonomy, derived from the right to self-determination embodied in section 12 of the Constitution[16] which refers to the right to bodily and psychological integrity, has been statutorily reinforced in the following sections of the NHA:[17] section 6 ‘User to have full knowledge’; section 7 ‘Consent of user’; section 8 ‘Participate in decisions’; section 11 ‘Health services for experimental and research purposes’ and section 71 ‘Research on or experimentation with human subjects’. In addition, section 16(1)(d) of the same Act provides that healthcare providers must inform patients of their right to refuse healthcare services, and that they need to explain the implications, risks and obligations attached to such refusal.

Patient autonomy, however, is not absolute and will be limited, depending on the circumstances. For example, patient consent to illegal or grossly negligent procedures (e.g. wanton experimentation) will be regarded as contra bonos mores, in other words, against the legal convictions of society or public policy. The consent of a fugitive to plastic surgery to mask his identity in order to escape prosecution is an example of invalid consent.[15] Patient autonomy is furthermore tempered by the implementation of the principles of beneficence, non-maleficence, justice

STEM CELL TOURISM and fairness, which, in the case of unproven therapies, may point to an obligation on the part of those providing the treatment to act in the best interests of the patient and not to cause harm. Registered healthcare providers who provide dangerous and unproven stem cell therapies may face disciplinary action from their respective professional bodies.[18]

Distributive justice The broad potential public benefit offered by stem cell research requires a consideration of difficult questions relating to social and distributive justice, in particular as far as access to these treatments is concerned. Patients in developing countries have limited access to cell therapy as a therapeutic option. Developing countries, such as SA, are facing many challenges in ensuring that basic medical services are established and maintained. The need for specialised forms of treatment, such as cell-based therapies, is therefore questioned.[19]

Regulation of stem cell treatments

International Society for Stem Cell Research (ISSCR) The International Society for Stem Cell Research is an independent, non-profit organisation that represents more than 4 000 members of the stem cell research community. The ISSCR’s Guidelines for the Clinical Translation of Stem Cells,[20] compiled by a group of stem cell researchers, ethicists, clinicians and regulatory officials from thirteen countries, condemns unproven use of stem cells or their direct derivatives to patients outside of a clinical trial, particularly when patients have to pay for such services.[21] As a matter of professional ethics, scientists, healthcare and research institutions should not participate in such activities. In countries where unproven therapies are offered, the regulators should work to prevent the exploitation of patients and, where relevant, take disciplinary steps against those clinicians involved and close down the fraudulent clinics. The ISSCR guides individuals in making informed choices when contemplating a stem cell-based intervention either locally or abroad.[22]

Professional ethical guidelines and medicoethical codes of conduct The conduct of doctors and the practice of medicine are governed by existing international and several national medico-ethical codes of conduct. Among national medico-ethical codes, the most important are the rules of conduct of the Health Professions Council of South Africa (HPCSA) and the guidelines on ethics for medical research of the South African Medical Research Council (MRC).

Some of the guidelines relevant to the provision of treatment which overlap with guidelines regarding research are the following: • Guidelines for Good Practice in the Health Professions (HPCSA, booklet 2):[23] ‘A practitioner shall in the conduct and scope of his or her practice, use only – (a) a form of treatment, apparatus or health technology which is not secret and which is not claimed to be secret; and (b) an apparatus or health technology which proves upon investigation to be capable of fulfilling the claims made in regard to it’ (par 19).

• Guidelines on Overservicing, Perverse Incentives and related matters (HPCSA, booklet 5):[23] ‘Health care practitioners shall not […] provide a service or perform procedures […] on a patient that are neither indicated nor scientific or have been shown to be ineffective, harmful or inappropriate through evidence-based review’ (par 3.1.1).

• General Ethical Guidelines for Biotechnology Research (HPCSA, booklet 7),[23] which contains instructive guidelines on a range of

activities in the context of biotechnology research, including stem cell research (but not its clinical translation).

• General Ethical Guidelines for Health Researchers (HPCSA, booklet 6):[23] ‘Health researchers should […] fully inform research participants about which aspects of medical care, if any, are related to health research, and clearly distinguish between therapeutic interventions and health research processes’ (par 6.6.4).

• Guidelines on Ethics for Medical Research (MRC, 2004),[24] which contain guidelines regarding research involving innovative therapy or intervention (par 5.10), as well as detailed guidelines regarding the conduct of clinical trials and the use of human tissue samples.

• Guidelines for Good Practice in the Conduct of Clinical Trials on Human Participants in South Africa (Department of Health, 2006),[25] which address general ethical issues with regard to clinical trials involving human participants.

Scientific experimentation and clinical trials, be they therapeutic or non-therapeutic, or beneficial to the patient or beneficial to others, are legally permissible provided they conform to the fundamental principles of informed consent to treatment, emergency treatment, the duty of reasonable care and with considerations of public policy in the particular circumstances.[26] Should an action for damages or a criminal charge flowing from harm allegedly suffered in consequence of improper or unacceptable experimentation arise, courts will be guided by the relevant ethical guidelines, such as those referred to above, as well as generally acknowledged international codes and declarations on human experimentation and a wide range of international declarations on human rights in general.[26]

Statutory framework The registration of medicines in South Africa is governed by the provisions and requirements of the Medicines and Related Substances Control Act[27] (MRSCA). The aim of the Medicines Control Council (MCC), a statutory body established in terms of the MRSCA, is to protect and safeguard the public by ensuring that all medicines sold and used in SA are safe, therapeutically effective and that these medicines meet relevant and acceptable standards of quality.[28] The MCC’s Guidelines for the Registration of Medicines: General Information[29] aim to assist applicants in the preparation of documentation for the registration of medicines for human use.[30] Legislation requires that the MCC shall register every medicine before it may be sold or marketed.[31] An application for the registration of a medicine should therefore be submitted for evaluation and approval.

The nature of a stem cell therapy is unique and different from conventional medicines. It may include characteristics and components of a ‘health service’, which include medical treatment,[32] ‘therapeutic’ or ‘non-therapeutic research’,[33] or ‘health services for experimental or research purposes, as described in the NHA.[34] Each of these has different legal and ethical considerations,[34] depending on whether one views cell-based therapy as a form of medical treatment, experimental research or medicine.[35] Stem cells used in HSC transplantation, essentially a stem cell intervention in existence for some decades as part of the treatment for certain haematological cancers and other disorders, are not registered with the MCC as a medicine, but an HSC transplantation requires, in addition to the written informed consent of the persons from whom the cells are removed, ministerial authorisation. [36]

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STEM CELL TOURISM The MCC prohibits the sale of medicine which is subject to registration but not registered.[37] An exception would be where such medicine is compounded in the course of the person carrying on of his or her profession by inter alia a medical practitioner for a particular patient, ‘in a quantity not greater than that required for treatment as determined by the medical practitioner’[38] A particular substance must be used relatively widely for therapeutic purposes and not only on a ‘single occasion’ in order for the substance to qualify as a ‘medicine’ in terms of the Medicines Act.[39] The Medicines and Related Substances Control Act (MRSCA) defines a medicine as: ‘any substance or mixture of substances used or purporting to be suitable for use or manufactured or sold for use in – (a) the diagnosis, treatment, mitigation, modification or prevention of disease, abnormal physical or mental state or the symptoms thereof in man; or (b) restoring, correcting or modifying any somatic or psychic or organic function in man, and includes any veterinary medicine.’[40] Biological medicines, a highly specialised class or type of medicine, produced using living organisms, are complex protein structures typically much larger than traditional chemical medicines and are mostly administered by injection.[1] An example would be insulin used for the treatment of diabetes. Biological medicines are more advanced than conventional therapies and provide prescribers with enhanced tools for treating patients.[41] Though clinically effective, these medicines are very expensive in SA.[41] The MRSCA does not define a biological medicine, but the guideline referred to above,[42] defines a biological medicine (categorised as a type of medicine) as follows: ‘A medicine where the active ingredient and/or key excipients have been derived from living organisms or tissues, or manufactured using a biological process. Biological medicines can be defined largely by reference to their method of manufacture (the biological process). These include inter alia medicines prepared from the following substrates: (i) Microbial cultures (fermentation); (ii) Plant or animal cell cultures (including those resulting from recombinant DNA or hybridoma techniques); (iii) Extraction from biological tissues; and (iv) Propagation of live agents in embryos or animals.

The living substrate may be genetically modified in a number of ways to provide the required active ingredient, including recombinant DNA technology or hybridoma techniques.

Biological Medicines include, but may not be limited to the following: (i) Plasma-derived products, e.g. clotting factors, immunosera, etc; (ii) Vaccines; (iii) Biotechnology-derived medicinal products (rDNA products) e.g. rHuantihemophilic factors, hormones, cytokines, enzymes, monoclonal antibodies, erythropoietins; (iv) Human gene therapy.’

Based on ii and iii in the first section above, a stem cell product (or stem cell application) would therefore fall within the ambit of a biological medicine.[43] It will, however, be important to be more explicit about stem cells and their applications in any revision of these guidelines in the future.

Moreover, as far as the harvesting of the stem cells for therapeutic use is concerned, the harvesting, isolation, cryopreservation and any other activity in relation to these cells must comply with the relevant

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requirements stipulated in chapter 8 of the NHA[44] and relevant regulations, such as the regulations relating to the use of human biological material. An example of a present regulatory inconsistency that creates many practical obstacles in respect of routine procedures, (e.g. bone marrow transplantation), is that the requirement of ministerial authorisation for the removal of stem cells from living persons (the latter being the step preceding the use of the cells for therapeutic purposes) is mentioned in the Act itself, but not in the regulations (relating to the use of human biological material).[45] The Regulations relating to Stem Cell Banks[46] furthermore state that no person may release stem cells products for therapeutic use unless this activity is authorised in terms of section 54 of the NHA and laboratory tests for certain transmissible diseases have been performed, where relevant.[47] In addition, no person may use stem cell products for therapeutic purposes unless he or she is registered with the department[48] and, among others, relevant written (and duly documented voluntary) consent has been obtained from the donor of the cells, even in the case of residual tissue, blood or blood products.[49] Since the MRSCA requires that the MCC shall register every medicine before it may be sold and marketed, an application for the registration of a medicine should be submitted for evaluation and approval.[50] Applications for registration of a medicine for use in humans are divided into different types for the determination of fees and allocation to reviewers for evaluation.[51] As such, a biological medicine is one of the types of medicines applications. It is a legal requirement that data submitted for evaluation, by the applicant, should substantiate all claims and should meet the technical requirements of quality, safety and efficacy. The MCC refers to international guidelines to be read in conjunction with the SA guidelines. In particular, the MCC refers to the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, the mission of which is to achieve greater harmonisation to ensure that safe, effective and high-quality medicines are developed and registered in the most resource-efficient manner.[52] The ICH promotes public health, prevents unnecessary duplication of clinical trials in humans, and minimises the use of animal testing without compromising safety and effectiveness.[53] Therefore, any applicant for the registration of a medicine must ensure that the technical requirements of quality, safety and efficacy of the product for the purposes for which it is intended, have been met. After submission of the relevant administrative steps for the registration of a medicine (including a biological medicine),[54] these biological medicines (containing or derived from living materials) require primary evaluation by the Biological Medicines Committee, in addition to other committees of the MCC. The MCC may choose to accept, defer, or reject the application. Should the application be deferred, the applicant will be required to produce additional information and re-submit the application for approval. Once the application is accepted, the biological medicine is registered with the MCC and may be sold and marketed.[1] Failure to register a stem cell therapy in the manner prescribed constitutes a contravention of section 14(1) of the MRSCA and hence an offence in terms of section 29, punishable by a fine or imprisonment of a period not exceeding 10 years.[55]

Conclusion The brief discussion of the relevant regulatory framework, as well as some of the attendant legal, ethical and scientific concerns and complexities, points to a need for an unambiguous and coherent legal framework for the regulation of cell therapy. This is borne out by the rise in unproven therapies globally. The unique nature of cell therapy makes the conventional

STEM CELL TOURISM medicines regulatory model a difficult fit for the proper legal regulation of this fast evolving and dynamic therapeutic field. Close scrutiny of chapter 8 of the NHA, including regulations promulgated in terms of the Act relevant to stem cell research and therapy, is required, to close any regulatory gaps that may facilitate the promotion of unproven cell therapies. Inconsistent or conflicting statutory provisions, regulations and guidelines governing both research and clinical application may inadvertently expose vulnerable patients to possible exploitation by bogus stem cell therapy operators.

As stated in the introduction, some physicians are already practising unregulated cell therapy in SA, with grave potential consequences. Access to novel therapies also raises pertinent issues regarding distributive justice and access to these treatments in a developing country where access to basic healthcare services is already severely compromised. Public educational programmes that provide the public with accurate and reliable information regarding legitimate and authentic existing cell therapies are critical, and should ideally include the provision of a platform (website or hot line) to which suspect stem cell activities could be reported.

Funding: This research and the publication thereof is the result of funding provided by the Medical Research Council of South Africa in terms of the MRC’s Flagships Awards Project SAMRC-RFA-UFSP-01-2013/ STEM CELLS.

References 1. Mahomed S, Slabbert MN. Stem cell tourism in South Africa: The legal position. S Afr J BL 2012;5(2):69-73. [http://dx.doi.org/10.7196/SAJBL.235] 2. Mahomed S. A legal framework for the regulation of stem cell research and therapy in South Africa. 2012. LLM dissertation, University of South Africa.

3. Republic of South Africa. Regulations on the Use of Human Biological Material.

Government Notice R177, Government Gazette 35099 of 2 March 2012. Pretoria: Government Printer, 2012: regulation 1.

4. Meissner-Roloff M, Pepper, M. Curbing stem cell tourism in South Africa. Applied & Translational Genomics (2013):22-27. [http://dx.doi.org/10.1016/j.atg.2013.05.001] 5. Master Z, Resnik DB. Stem cell tourism and scientific responsibility. EMBO Rep 2011;12(10):992-995. [http://dx.doi.org/10.1038/embor.2011.156].

6. International Society for Stem Cell Research. Guidelines for the Clinical Translation of Stem Cells. ISSCR 3 December, 2008). http://www.isscr.org/docs/ guidelines/isscrglclinicaltrans.pdf (accessed 1 February 2015).

7. Lysaght T, Kerridge I, Sipp D, et al. Oversight for clinical uses of autologous adult stem cells: Lessons from international regulations. Cell Stem Cell 13, 2013;13(6)::647-651. [http://dx.doi.org/10.1016/j.stem.2013.11.013].

8. Bateman, C. ‘Pioneer’ Paarl neuro sets alarm bells ringing. S Afr Med J 2013; 103(1):8-9. [http://dx.doi.org/10.7196/SAMJ.6587] 9. Du Toit DF, Liebenberg WA. Somatic-cell nuclear transfer: Autologous embryonic intra-spinal stem cell transplant in a chronic complete quadriplegic patient.

Neuro-anatomical outcome after one year. Revista Argentina de Anatomía Clinica 2014;6(1):35-42.

10. Hyun I, Lindvall O, Ahrlund-Richter L, et al. New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell 2008;3(6):607-609. [http://dx.doi.org/10.1016/j.stem.2008.11.009] 11. Venter v. Roche Products (Pty) Limited and Others. Western Cape High Court of South Africa, 12285/08. Judgement delivered on 7 May 2013.

12. Republic of South Africa. National Health Act 61 of 2003. Pretoria: Government Printer, 2003: section 73.

13. Republic of South Africa. National Health Act 61 of 2003. Pretoria: Government Printer, 2003: section 72.

14. Castell v. De Greef 1994 (4) SA 408 (C) at 420-421.

15. Slabbert MN. Medical Law: South Africa. In: Nys H, ed. International Encyclopaedia of Laws. Alphen aan den Rijn, NL: Kluwer Law International, 2014: par 125.

16. Republic of South Africa. Constitution of the Republic of South Africa, 1996.

Pretoria: Government Printer, 1996.

17. Republic of South Africa. National Health Act 61 of 2003. Pretoria: Government Printer, 2003: , sections 6-8, 11, 16(1)(d) and 71.

18. Republic of South Africa. Health Professions Act 56 of 1974. Pretoria: Government Printer, 1974: , section 3.

19. Jackson CS, Pepper MS. Opportunities and barriers to establishing a stem cell programme in South Africa. Stem Cell Research & Therapy 2013;4(3):54:1-7 [http://dx.doi.org/10.1186/scrt204].

20. International Society for Stem Cell Research. Guidelines for the Clinical Translation of Stem Cells. ISSCR, 3 December, 2008). http://www.isscr.org/docs/

guidelines/isscrglclinicaltrans.pdf (accessed 1 February 2015).

21. International Society for Stem Cell Research. Guidelines for the Clinical Translation of Stem Cells. ISSCR 3 December, 2008 at 5. http://www.isscr.org/ docs/guidelines/isscrglclinicaltrans.pdf (accessed 1 February 2015).

22. International Society for Stem Cell Research. Guidelines for the Clinical Translation of Stem Cells. ISSCR, 3 December, 2008 at 4. http://www.isscr.org/ docs/guidelines/isscrglclinicaltrans.pdf (accessed 1 February 2015).

23. Republic of South Africa. Health Professions Council of South Africa. Pretoria: HPCSA, 2008.

24. Republic of South Africa. Medical Research Council. Cape Town: MRC, 2004.

25. Republic of South Africa. Pretoria: National Department of Health, 2006.

26. Slabbert MN. Medical Law: South Africa. In: Nys H, ed. International Encyclopaedia of Laws. Alphen aan den Rijn, NL: Kluwer Law International, 2014: par 292.

27. Republic of South Africa. Medicines and Related Substances Control Act 101 of 1965. Pretoria: Government Printer, 1965.

28. Republic of South Africa. Medicines Control Council. http://www.mccza.com (accessed 21 February 2015).

29. Republic of South Africa. Medicines Control Council. Guidelines for the Registration of Medicines: General Information. Pretoria: Government Printer, 2012.

30. Republic of South Africa. Medicines Control Council. Guidelines for the Registration of Medicines. Pretoria: Government Printer, 2012:par 1.

31. Republic of South Africa. Medicines and Related Substances Act 101 of 1965.

Pretoria: Government Printer: section 14.

32. Republic of South Africa. National Health Act 61 of 2003. Pretoria: Government Printer, 2003: section 1.

33. Republic of South Africa. National Health Act 61 of 2003. Pretoria: Government Printer, 2003: sections 71(2) and 71(3).

34. Republic of South Africa. National Health Act 61 of 2003. Pretoria: Government Printer, 2003: section 11.

35. Van Wyk C. Legal issues surrounding stem cell research, including consent.

Unpublished paper delivered at the conference on Legal Aspects relating to the Applications of Biotechnology, University of South Africa. 21 August 2012:9-11.

36. Republic of South Africa. National Health Act 61 of 2003. Pretoria: Government Printer, 2003: section 56.

37. Republic of South Africa. Medicines and Related Substances Act 101 of 1965.

Pretoria: Government Printer, 1965: section 14(1).

38. Republic of South Africa. Medicines and Related Substances Act 101 of 1965.

Pretoria: Government Printer, 1965: section 14(4).

39. Reitzer Pharmaceuticals (Pty) Ltd v. Registrar of Medicines and Another 1998 (4) SA 660 (T) at 682-3.

40. Republic of South Africa. Medicines and Related Substances Act, section 1(1) .

Government Gazette 1965.

41. Carapinha, JL. Policy guidelines for risk-sharing agreements in South Africa. SA Fam Pract 2008; 50(5):43-46.

42. Medicines Control Council. Guidelines for the Registration of Medicines: General Information. Pretoria: Government Printer, August 2012: par 2.7.5.

43. Jordaan D. Regulatory crack-down on stem cell therapy: What would the position be in South Africa? S Afr Med J 2012;102(4):219-220.

44. Republic of South Africa. National Health Act 61 of 2003. Pretoria: Government Printer, 2003: sections 6; 11, 55, 56(2)(a)(iv), 56(2)(b), and 56(2)9(b)).

45. Republic of South Africa. Government Notice R177 in Government Gazette 35099 of 2 March 2012. Pretoria: Government Printer, 2012.

46. Republic of South Africa. Goverment Notice R183 in Government Gazette 35099 of 2 March 2012. Pretoria: Government Printer, 2012: regulation 2.

47. Republic of South Africa. Regulations relating to Stem Cell Banks. Government Notice R183 in Government Gazette 35099 of 2 March 2012. Pretoria: Government Printer, 2012: regulation 2(1).

48. Republic of South Africa. Regulations relating to Stem Cell Banks. Government Notice R183 in Government Gazette 35099 of 2 March 2012. Pretoria: Government Printer, 2012: regulation 3(3)(a).

49. Republic of South Africa. Regulations relating to Stem Cell Banks. Government Notice R183 in Government Gazette 35099 of 2 March 2012. Pretoria: Government Printer, 2012: regulation 2(3).

50. Republic of South Africa. Medicines Control Council. Guidelines for the Registration of Medicines. Pretoria: Government Printer, 2012: par 2.7.

51. Republic of Souh Africa. Medicines Control Council. Guidelines for the Registration of Medicines. Pretoria: Government Printer, 2012: par 2.7.

52. Kuhnert, BR. Global Forum; 2011;3(2):17. http://www.google.co.za/url?url=http:// www.ich.org/fileadmin/Public_Web_Site/News_room/C_Publications/DIA_Global_ Forum_Harmonization_articles_l_2011pdf&rct=j&frm=1&q=&esrc=s&sa=U&ved=0 CBMQFjAAahUKEwjporix6ujGAhUDcNsKHUjPDdg&sig2=fDFfjJVW3jqAJZkREkMu9 A&usg=AFQjCNEnnzYNTJ3buztIbpDT69q4msra9A (accessed 20 July 2015).

53. ICH: Harmonisation for better health. FAQ. Switzerland. http://www.ich.org/ about/faqs.html (accessed 28 July 2012).

54. Republic of South Africa. Medicines Control Council. Guidelines for the Registration of Medicines. Pretoria: Government Printer, 2012: paras 3 and 4.

55. Republic of South Africa. Medicines and Related Substances Act 101 of 1965.

Pretoria: Government Printer, 1965.

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INFORMED CONSENT

Towards guidelines for informed consent for prospective stem cell research J Greenberg,1 PhD; D C Smith,1 PhD; R J Burman,2 BSc Hons; R Ballo,3 PhD; S H Kidson,3 PhD Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa 2 MRC/UCT Receptor Biology Unit, Division of Medical Biochemistry, Department of Integrated Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, South Africa 3 Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, South Africa 1

Corresponding author: J Greenberg (Jacquie.greenberg@uct.ac.za)

Stem cell science is advancing at an unprecedented rate, with thousands of research papers being published every year and many clinical trials for a wide range of conditions underway as registered on ClinicalTrials.gov. This rapidly expanding and alluring field has brought with it ever more complex and multifaceted ethical issues, many of which require new guidelines, consent protocols and even change in legislation, since they do not fit comfortably in the existing bioethical regulations and protocols. Keeping up with the ethical implications of stem cell research is daunting to the expert and non-expert. We review the various types of stem cells and then focus on multipotent and pluripotent cell types, since it is these cell types that bring with them the greatest research and therapeutic potential, while concurrently delivering novel ethical conundrums. Certain key considerations are currently lacking and what is needed is how to obtain permission from individuals who donate their biological material for both scientific inquiry and eventually, for their potential therapeutic utility.

S Afr J BL 2015:8(2 suppl 1):46-48. DOI:10.7196.sajbl.8408

Stem cells have been classified broadly into three categories: • Adult stem cells • Multipotent mesenchymal stem cells • Pluripotent stem cells, including embryonic stem (ES) cells and induced pluripotent stem cells (iPSCs).

Skin epidermal cells (keratinocytes) are a typical example of adult stem cells; they can be harvested from donor skin samples, cultured in vitro and used for research or for treatment, such as for burns.

These unipotent adult cells can only be grown into skin cells and are covered in current consent protocols. In contrast, mesenchymal stem cells can be obtained from a variety of tissues, including bone marrow, umbilical cord, fetal and adipose tissues. Bone marrow cells have been used for treating haematological conditions for over 70 years. The transplanted cells home into and populate the recipient’s bone marrow and when successful, differentiate into all the blood cell types. Many studies have shown these cells to differentiate into several different cells types in culture, including adipocytes, chondrocytes and osteoblasts.[1] Mesenchyme stem cells also seem to have the ability to modulate inflammatory reactions, and are being used in treatment trials for pathologies resulting from, for example, lung injury, myocardial infarction, diabetes, sepsis and stroke.[2] Pluripotent stem cells are capable, at least in vitro, of differentiating into all the types of cells in the body. However, the ability of pluripotent cells to become a part of a fully functional normal tissue remains to be proven, though many animal studies and some human studies provide exciting prospects.[3] Human embryonic stem (hES) cells obtained from the inner cell mass of the blastocyst can be considered as the ‘gold standard’ of pluripotency, but because

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embryos must be destroyed to obtain these cells, the harvesting and use of hES cells is limited by their availability and is constrained and regulated by complex ethical and moral issues.[4] The stem cell community was therefore greatly excited when, in 2006, Takahashi and Yamanaka showed that it was possible to ‘reprogramme’ fully mature differentiated cells back into pluripotency by the addition of genes that reactivate the embryonic genetic programme.[5,6] We, and many groups around the world, immediately saw the potential of these cells to study development and have established ‘disease-in-the-dish’ models to help elucidate the cellular aetiology of diseases and for patient-specific drug-testing studies.[7] With the rapid exploration of iPSC technology and the burgeoning research output, it is not surprising that the first trial of iPSC for the treatment of agerelated macular degeneration is underway.[8] However, the rise of iPSC technology has brought into focus many new ethical questions that must be addressed and resolved.

Ethics Medical research involving human subjects or human biological material should be designed to promote the best interests of the study participants. Disclosure of research protocols which affect the participant directly and in some instances, indirectly, is nonnegotiable and should be communicated to participants in such a manner that they have no uncertainties about their rights in the study. The methods of conveying this information to participants are open to much debate and the World Medical Association (WMA) has developed the declaration of Helsinki (DoH) as a statement of ethical principles which should govern medical research on human subjects and identifiable human biological material.[9] Although primarily addressing physicians, the DoH policy is widely used by scientific

INFORMED CONSENT researchers and underpins the informed consent (IC) requirement for ethical approval

by Human Research Ethics Committees (HRECs) at academic institutions.

In South Africa (SA), we propose that IC guidelines for stem cell research should attempt to cover all the aspects in the DoH. This should take into account the local challenges resulting from the diversity of culture, religion and socioeconomic status of the subjects in SA and in Africa.

However, regardless of how carefully the IC is worded, the implementation of the recommendations of the DoH relies on the researchers’ truthfulness, humanity, respect for others and sensitivity to social and cultural issues. Without a continuous audit of the study progress and of the researchers’ adherence to the IC commitment, ethical deviations may escalate.

Consent guidelines Whether or not one agrees that individual consent is warranted for any cell type derived from a patient’s sample, a more fundamental issue revolves around the patient’s competency in making the decision to allow for the use of their biological material. Stem cells pose challenges that the standardised IC documents for collection of blood and DNA often do not address. A case in point is the generation of iPSCs with their potential to become any cell type in the body and therefore the long-term potential use for these cells in clinical translational studies in the future.[5,6] It is almost im­ possible to provide accurate information about the path that iPSCs will traverse in their lifetime, given the rapid advances in this field.[10] However, when conveying information to study participants, efforts should be made to be explicit regarding current controversial issues in this regard.

For example, it should be stated that germ line cell derivatives and reproductive applications will not be attempted or developed with the generated iPSCs, and one should provide the reassurance that current legislation prohibits certain uses of biological samples, such as the reproductive cloning of humans (National Health Act 61/2003: 57(1)). In SA, with its social challenges and significant rate of illiteracy, how does one convey information to a layperson about the reprogramming of somatic cells back to their embryonic state?

We believe that the emphasis must be on ensuring that the relevant information is imparted in a clear and simple manner and in the appropriate language. Innovative ways of communication may be required.

Moreover, it is noteworthy that in Japan, the Japanese Minister of Health, Labour and Welfare has initiated a ‘new five-year clinical trial activation plan’ running roleplay workshops on IC to boost public understanding of clinical trials with stem cells (see Kusenose et al. in this edition).

The University of Cape Town (UCT), Human Research Ethics Committee (HREC) has the following recommendations for

IC during the collection and storage of biological material from human subjects and recommends the use of videotapes, photographs or diagrams of research procedures, pre-visits to the research site to see equipment, group discussions, web sites and comics that explain the nature of the research where applicable; as well as brochures and guidance on participants’ rights in research (see the UCT FHS HREC website re human ethics standard operating procedures).

As stem cell research is so complex, it may be difficult for patients to comprehend what exactly scientists are attempting to

Table 1. Issues to address when compiling informed consent forms for stem cell related research (based on recommendations by Lowenthal et al.[13] 2012) Point

Details

Purpose of the study

Give a description of the study. This may be detailed if the samples are intended for a specific project, or broader in the case of a larger undefined study.

What are iPSCs/ mesenchymal stem cells/haematopoietic stem cells/adult stem cells?

Provide a simple explanation of the type of cell that will be obtained, and a description of the potential uses of the cell type (for example, disease modelling and drug testing).

Details of participation

Describe what type of donation will be required (skin biopsy, blood sample, hair sample, cord blood).

Collection of medical/ clinical information

Outline what medical information will be requested from the individual, such as age, sex, family history of disease.

Number and frequency of visits required

State whether a single sample will be donated in one visit, or if multiple samples will be collected over a period.

Re-contact

State whether the participant may be re-contacted in the future to obtain additional consent for future projects, to update the participant on the progress of the research, or to obtain additional health-related information.

Limitations on use of cells

Describe the limitations of the use of the donated cells. It may be useful to state that all research will comply with applicable federal and institutional laws and policies.

Risks

Outline any risks associated with the applicable medical procedure (skin biopsy or blood donation, etc).

Confidentiality

Describe the plans and policies in place to protect the confidentiality of the donor, such as password-protected databases, coding, and restricted access to lab areas.

Benefits

Will there be direct benefit to the donor or their family, or simply to the scientific community?

Options

State that participation is voluntary.

Amendments to consent

Describe what options the donors have if they change their mind. Can the sample be withdrawn? Can the material be de-linked from the donor?

Payment

State whether the participant will be compensated for their participation. You may wish to include a clause about financial compensation regarding any future commercial products.

Problems or questions

Provide the details of a person and/or group whom the donor may contact if they have any further questions or concerns.

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INFORMED CONSENT do with a developing technology, which is still often in the unknown. Therefore, there is now an urgent need for professionally trained staff in SA, who are able to objectively explain the risks and benefits of stem cell research to study participants and highlight the value of their possible future participation in clinical trials.

These trained experts could be described as stem cell counsellors who could help potential participants navigate through trials; explain risks, benefits, and therapeutic alternatives; and provide information about unproven transplants offered outside the bounds of good clinical practice and ethical research. They would also need to work closely with patients enrolled in clinical trials and serve as a public resource for patient education, advocacy and outreach efforts.[11] The reason is that despite the dramatic development of gene- and stem cell-based therapies in ophthalmology, for example, there are still major concerns that need to be addressed concerning the promise and pitfalls of communicating these facts to patients as the clinical research progresses. At present they could, at best, represent a treatment but not a cure and are, as yet, certainly not ‘risk-free’.[12] The generation of iPSCs has great potential for future research and the scope and extent of their use is limitless. However, it is impossible to anticipate the full range of their future application.

Therefore, regarding prospective collection of biological material for future research of this nature, we propose that the consent form should be used prudently to assure participants of the ethical use and governance of their specimens in SA, as was proposed by Lowenthal et al.[13] Some guidelines should be formulated for an ethical approach to obtaining comprehensive IC for the collection of biological material for the generation of iPSCs for prospective research purposes. Broadly, the recommended issues to be addressed in IC forms, incorporating requirements for stem cell research, are given in Table 1.

The approach to obtaining IC for stem cell research may be considered as a spectrum. On the one end, consent may be obtained for a broad, open-ended study, which requires a single interaction with the research participant. While this type of consent may be facilitative for future research purposes, it can be questioned whether this truly embodies ‘informed’ consent, since the full extent of future stem cell research potential cannot be predicted. The narrow approach to IC can be considered to lie on the other end of the spectrum, where participants give consent for their material to be used for a very specific purpose. Lowenthal et al[13] suggest that an IC ‘middle ground’ can be reached, which allows for broad aims, but with clear boundaries with regard to future research.

This approach relies on a constant dialogue with participants, and re-consenting may be required in some cases. Institutions may also consider a tiered approach to consent, which uses an opt-in or -out system that allows participants to tailor their consent, but would require added oversight and monitoring regarding the use of individual cell lines. There is the also the question of unlimited use of de-identified samples for research purposes that needs to be considered.[14] The issue of privacy and confidentiality is a major area of concern to potential research participants, given that true de-identification of biological material and/or data is not always possible, since a small number of genetic variants can uniquely identify the donor. The protection and respect of research participants’ privacy is of paramount importance.[14]

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In 2009 Aalto-Setälä and colleagues discussed that the development of iPSCs had reshaped and revolutionised the scientific and political arenas of stem cell research.[15] They proposed that iPSCs had provided many novel scientific opportunities to study the pathophysiology of diseases that had hitherto been impossible. iPSCs have enabled scientists to understand more about stem cell biology, identify new therapeutic targets and facilitated the testing of novel therapies in vitro.

Therefore a wait-and-see approach to the therapeutic use of iPSCs is proposed. In SA the focus should fall on the use of iPSCs as disease-ina-dish models, and that for now we must determine their efficacy and safety by using them as pre-clinical cellular models. This time should be used constructively and productively to possibly develop prospective policies for the use of iPSCs for therapeutic transplantation in the future and also to address the scientific, legal and ethical implications of establishing and using iPSCs in the laboratory.[10] For SA to continue to develop the capacity to incorporate new biomedical technologies, it must become proactive in formulating clear guidelines for the oversight of IC for future anticipated and as yet, unanticipated use of multipotent and pluripotent stem cells in research.

Funding. This research and the publication thereof is the result of funding provided by the Medical Research Council of South Africa in terms of the MRC’s Flagship Awards Project SAMRC-RFA-UFSP-01-2013/STEM CELLS.

References 1. Charboard P. Bone marrow mesenchymal cells: Historical overview and concepts. Hum Gene Ther 2010;21(9):1045-1056. [http://dx. doi.org/10.1089/ hum.2010.115] 2. Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): Role as guardians of inflammation. Mol Ther 2012;20(1):14-20. [http://dx.doi.org/10.1038/ mt.2011.211] 3. Xu XL, Yi F, Pan HZ, et al. Progress and prospects in stem cells therapy. Acta Pharmacol Sin 2013:34(6):741–746. [http://dx.doi.org/10.1038/aps.2013.77] 4. Patil AM. Embryonic stem cell research: Ethical and legal controversies. J Indian Acad Forensic Med 2014; 36(2):188-194.

5. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006:126(4):663676. [http://dx.doi.org/10.1016/j.cell.2006.07.024] 6. Takahashi K, Tanabe K, Ohnuki M. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007;131(1):1-12. [http://dx.doi. org/10.1016/j.cell.2007.11.019] 7. Ballo R, Greenberg LJ, Kidson SH. A new class of stem cells in South Africa: iPS cells. S Afr J Med 2012;103(1):16-17 [http://dx. doi.org/10.7196/SAMJ.6604] 8. Ramsden CM, Powner MB, Carr AJ, Smart MJ, da Cruz L, Coffey PJ. Stem cells in retinal regeneration: Past, present and future. Development 2013;140(12):25762585. [http://dx.doi.org/10.1242/dev.092270] 9. World Medical Association. World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA 2013;310(20), 2191-2194. [http://dx.doi.org/10.1001/jama.2013.281053] 10. Greenberg J, Smith D, Pope A. Stem cells on South African shores: Proposed guidelines for comprehensive informed consent. S Afr Med J 2013;103(1):6. [http://dx.doi.org/10.7196/SAMJ.6532] 11. Scott CT. The case for stem cell counselors. Stem Cell Reports 2015;4(1):1-6. [http://dx.doi.org/10.1016/j.stemcr.2014.10.016] 12. Benjaminy S, Kowal SP, MacDonald IM, Bubela T. Communicating the promise for ocular gene therapies: Challenges and recommendations. Am J Ophthalmol 2015 May 30. pii: S0002-9394(15)00311-6. [http.dx.doi.org/10.1016/j.ajo.2015.05.026] [Epub ahead of print] 13. Lowenthal J, Lipnick S, Rao M, Chandros Hull S. Specimen collection for induced pluripotent stem cell research: Harmonizing the approach to informed consent.

Stem Cells Transl Med 2012;1(5):409-421. [http://dx.doi.org/10.5966/sctm.20120029] 14. Hudson KL. Genomics, health care, and society. N Engl J Med 2011;365(11):10331041. [http://dx.doi.org/10.1056/NEJMra1010517] 15. Aalto-Setälä K, Conklin BR, Lo B. Obtaining consent for future research with induced pluripotent cells: Opportunities and challenges. PLoS Biol 2009;7(2): e42. [http://dx. doi.org/10.1371/journal.pbio.1000042]

INFORMED CONSENT

Informed consent in clinical trials using stem cells: Sugges­ tions and points of attention from informed consent training workshops in Japan M Kusunose,1 MA, MBE; F Nagamura,2 MD, PhD; K Muto,1 PhD 1 2

Department of Public Policy, Institute of Medical Science, University of Tokyo, Japan Department of Advanced Medicine Promotion, Institute of Medical Science, University of Tokyo, Japan

Corresponding author: M Kusunose (mayumi.kusunose@fulbrightmail.org)

Informed consent (IC) is an essential requirement of ethical research involving human participants, and is usually achieved by providing prospective research participants (PRPs) with a document that explains the study and its procedures. However, results of a series of IC workshops held in Tokyo during 2014 indicate that consent forms alone are not enough to achieve full IC in regenerative medicine research, due to the necessity of long-term patient-safety observations to meet the ethical challenges of such research. Adequate training of the people who are responsible for obtaining IC (elucidators) is also necessary to ensure full IC. Elucidators must be able to provide PRPs with sufficient information to ensure adequate comprehension of the study and its potential after-effects; judge PRPs’ voluntariness and eligibility; and establish and/or maintain partnerships with PRPs. The workshops used role-playing simulations, to demonstrate how to effectively obtain fuller IC, to members of several Japanese research groups preparing for clinical stem cell trials. Workshop results were correlated with the results of a 2013 workshop on what information patients want when considering participation in induced pluripotent stem cell (iPSC) research. The correlated results showed the need for continuous training and education of elucidators in order to make sure that they acquire and maintain IC competency.

S Afr J BL 2015;8(2 Suppl 1):49-54. DOI:7196/SAJBL.8016

The world’s first-in-human (FIH) clinical trial using induced pluripotent stem cells (iPSCs) was conducted in Japan in 2014.[1,2] Stem cell clinical trials have raised concerns over a variety of ethical issues including: how well prospective research participants (PRPs) have been informed about the nature of the trials, patients’ therapeutic misconceptions about the trials, and the need for long-term safety observations of trial participants. These and other scientific issues associated with iPSCs distinguish research in regenerative medicine from ordinary research on therapeutic developments and have led to questions on how well the typical informed consent (IC) process works for these trials.

Informed consent is an essential requirement of ethical research involving human participants, and contains three key components: information, comprehension, and voluntariness.[3] Usually IC is achieved by providing PRPs with a document that explains the study and its procedures. However, transplanted cells differentiated from iPSCs as they were genetically manipulated and long-term observation of trial participants is mandatory for early detection of unknown side effects. We need to put greater emphasis on informing participants about the nature of the trial and the potential after-effects. Informed consent documents cannot always anticipate all participant informational needs, increasing the importance of question and answer sessions between PRPs and those responsible for obtaining full IC. One way to address IC incompleteness is establishing standards for IC documents and procedures. Several organisations have suggested standards and guidelines for more fully informing PRPs in order to ensure a clear understanding of IC associated with stem cell research.

The International Society for Stem Cell Research (ISSCR) propose the following guidelines: • Patients need to be informed when stem cell-derived products have never been tested before in humans and if researchers do not know whether they will work as hoped.

• Cell-based interventions, unlike many pharmacological products or even many implantable medical devices, may not leave the body and may continue to generate adverse effects for the lifetime of the patient. The possible irreversibility of a cellular transplant should be explained clearly.

• Subjects should be informed about the source of the cells so that their values are respected.

• Ensuring subject comprehension must be done at each phase of the clinical trials process. Ideally, the subject’s comprehension of information should be assessed through a written test or an oral quiz during the time of obtaining consent.

• Human subjects’ research committees should ensure that informed consent documents accurately portray these uncertainties and potential risks, and clearly explain the experimental nature of the clinical study.[4] Aalto-Setälä et al [5] suggest guidelines that permit PRPs’ participation in stem cell research only if they agree to specific conditions: genetic modification of cells; injection of iPSCs or their derivations into nonhuman animals, including injections into the brain; sharing cell lines with other researchers with appropriate confidentiality protection; and patenting scientific discoveries and developing commercial tests and therapies, with no sharing of royalties with cell donors.

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INFORMED CONSENT Each recommendation brings different ethical concerns to any discussion about IC reforms. The many ethical problems revealed in the recommendations show that improving IC related to stem cell research is a pressing issue that needs to be resolved to protect research participants.

Purpose

Table 1. Drafting consent forms • Introduction • What is a clinical trial?

• Cartilage damage in knee • Treatment of the knee joint

This paper examines the results of a series of workshops conducted in 2014 to determine specific areas of concern regarding IC and to identify methods to address these concerns. Workshop results are then compared to a 2013 workshop that studied what information is wanted by patients when considering participation in iPSC research. Each study was concerned with different aspects of the role elucidators play in achieving full IC. For the purpose of this paper, we have defined ‘elucidators’ as ‘people who obtain and are in charge of IC’, even though IC is usually conducted by investigators, physicians, research nurses, or clinical research coordinators.

• About this clinical trial and its objective

Method

• Benefits

Workshops on IC in clinical trials using stem cells were conducted in Tokyo in February and November 2014. We accepted applications for the workshops from Japanese research groups enrolled in the ‘Highway Program for the Realization of Regenerative Medicine’, funded by the Japan Science and Technology Agency, who planned to conduct stem cell clinical trials in the near future. All participants conduct or support the IC process for PRPs or prepare consent forms for their research groups.

Prof. Sean Philpott-Jones, Director of the Bioethics Program/ Director of the Research Ethics Program for the Bioethics Program at Union Graduate College – Icahn School of Medicine at Mount Sinai in New York, was invited to lead the workshop. Prof. PhilpottJones has extensive experience with IC education using role-play methods. As part of the workshop preparation process, consent forms were carefully drafted to incorporate comprehensive information related to IC (Table 1) and the forms were distributed to the workshop participants (WPs) a week before the workshop began.

The February workshop served as a pilot study to obtain feedback from participants regarding workshop forms and procedures. Seven people participated in the four-and-a-half hour workshop. One male and one female from a group of volunteers, helping medical students prepare for the Objective Structured Clinical Examination (OSCE), acted as patients. WPs acted as IC elucidators. Two consent forms were prepared for the workshop: ‘Transplant of Chondrocytes Derived from Autologous Bone Marrow Mesenchymal Stem Cells (MSCs) for Cartilage Damage in Knee Joints (Phase I Trial)’ (educational material) and ‘Clinical Research on Autologous iPS Cell-Derived Retinal Pigment Epithelium Sheet Transplantation for Exudative Age-Related Macular Degeneration’ (a real consent form from the clinical trial).

Feedback, following the pilot workshop, led to the creation of a new IC form for the ‘Transplant of Chondrocytes’ and to the recruitment of better performers as workshop patients.

In November, six people participated in a six-hour workshop. Two of the six had participated in the first workshop. For this workshop two female actors from an entertainment agency played the patients.

As part of using the new IC form, bogus patient information and referrals were created to preserve confidentiality.

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• Methods of the clinical trial • Selection criteria for research participants of this clinical trial • Period and planned number of participants of this clinical trial • Study site • Study method • Risks • Treatments other than this clinical trial • Treatments after completion of this clinical trial • Disadvantages • Expense for participation in this clinical trial • Treatment and coverage for health hazards caused by this clinical trial • Privacy protection • When we obtain new information on this clinical trial • Consent for participation in this clinical trial • Right of consent withdrawal • Discontinuation of this clinical trial • Specimen storage for safety check • Access to records • Intellectual property right • Conflict of interest • Funding sources of this clinical trial • Contact information and consultation service • Complaints counter • Clinical research coordinators • Address of discontinuation request

Both workshops used role-playing to teach how to obtain IC from PRPs. Volunteers and/or actors played patients. Characteristics, background, and medical conditions of the ‘patients’ were created in detail before­ hand so that the translational-research physician could play their parts realistically. In the workshop held in November (the MSC case), one actor played a woman whose husband had told her to participate in the trial so that she could get better and do more housework (Fig. 1). In the iPSC case, an actor played a young actor who did not want surgical scars on her body because of her occupation and was also struggling financially, which made her eager to try clinical trials; the character also wished to have a baby in the near future (Fig. 2). Both actors were required to ask specific questions, such as could they participate if pregnant, and were encouraged to ask for explanations for any jargon used during the session. They were also free to ask questions about anything else that they believed would help them decide whether to participate (except for specific medical issues that the clinical trials were not designed to treat).

INFORMED CONSENT

11/07/2014 Dear Professor Taro Bando, I would like to discuss one of our patients, Ms. xxxx. Though she has been treated at our hospital as an outpatient due to cartilage damage in her knee joints, she has also received conservative medical therapy as described below. However, she is now in thinking of surgical therapy due to disabling symptoms and other occupational reasons.

Alternative therapies are autologous transplantation (‘mosaicplasty’), in which a part of the non-damaged knee cartilage is obtained and transplanted into the damaged area in order to facilitate the regeneration of hyaline cartilage; the use of autologous cultured cartilage called JACC which has been approved as regenerative medicine; and artificial joint replacement. I have also suggested transplantation of chondrocytes derived from autologous bone marrow mesenchymal stem cell for cartilage damage in knee joint.

When I told her about the research that was done with the second research subject, she told me she would like to hear about your clinical trial. I gave her a brief explanation but did not hand her a copy of the consent form. I would appreciate it if you could inform her about the clinical trial.

Patient information Name: xxxxxxxx, Age 46 y/o, ID # xxxxxxxxx Contact information: Address: xxxxxx Phone: # xxxxxx Occupation: Tea ceremony instructor (runs a tea ceremony school at home) Family history: Husband (physician), son, daughter, no special instructions Anamnesis: No special instructions Progress Six months ago, when walking, she was knocked down and injured by a motorcycle driver. Bruise and torsion caused by the fall led to three days of hospitalization, during which the affected area was immobilized and kept under observation. Currently, she is under treatment for tibial cartilage damage as an outpatient.

For cartilage damage, the following are conducted: internal use of anti-inflammatory analgesic, intra-articular administration of steroid and hyaluronan once a week, and drainage of joint fluid when needed. Tumentia is slight; however, she complains of severe pains whenever she has to move about.

Special instructions She is a tea ceremony instructor and is eager to continue managing her tea ceremony school. However, she cannot go down on her knees due to the limitations in her knee range motion, and so she is face with the prospect of closing her business. Therefore, she wants therapy so that she can continue to work as an instructor at her tea ceremony school. Her husband is a physician. It seems that he is positively reinforcing her participation in the clinical trial and expecting her early recovery. She, on the other hand, has a propensity for anxiety, and she appears to have a fear of invasive therapy such as removal of autologous cartilage.

Professor Kazuo Ohmori, MD Orthopaedist

Fig. 1. Patient information sheet – patient 1

11/07/2014 Dear Professor Bando, I would like to introduce a patient, Ms. xxxx . She is in outpatient treatment at our hospital for cartilage damage in the keen joint, sustained in a traffic accident. Thus far, she has received conservative medical therapy; however, due to her disabling symptoms, I suggested to her that at this stage she might consider seeking surgical therapy. I explained a number of potential therapies, as follows: 1) anaplasty of the damaged area using an arthroscope (reducing physical stimuli by removing processus), 2) drilling or microfracture (methods of bone marrow stimulation, which arthroscopically resect the subchondral bone), 3) mosaicplasty (autologous transplantation of knee cartilage), 4) autologous cultured car­ ti­lage called JACC which is a medical product for regenerative medicine and 5) artificial joint replacement. My recommendation was that the final option, artificial joint replacement, is the most realistic; options 1-4 would not offer a comprehensive remedy, due to the large size of the damaged area. However, Ms. xxxx is still young. If she opts for artificial joint replace­ ment, she will require several additional replacement surgeries in the future, which will result in large scars. Additionally, bone malformation caused by the artificial joint will cause surgical difficulties to increase with each operation. Ms. xxxx is an active professional actor, and as such wants to keep scarring to a minimum. She is interested in treatment via chondrocytes derived from autologous iPS cells, a procedure she heard of through the press. She has stated that she would like to learn more about your clinical trial. I have explained the trial broadly, but have not given her a copy of the consent form. Treatment options 3 and 4 will be difficult to conduct because of the extent of the damaged area; however, I assume that it is possible to secure the necessary cell numbers if regenerative therapy with using iPS cells. I have also explained to her that there is no one who received this method. I thank you in advance for your support.

Patient information Name: xxxxxx Age: 29 y/o ID #: xxxxxx Contact address: xxxxxx Contact phone #: xxxxxx Occupation: Actor Family history: Single / no special instructions Anamnesis: No special instructions Progress Three months ago, the patient collided with a vehicle while bicycling.

She was hospitalised at our facility to immobilise the affected area, and received follow-up care for two weeks. Currently, she is under treatment as an outpatient.

In the outpatient department, the following therapies are conducted: administration of internal anti-inflammatory analgesics; once weekly trial implementation of intra-articular steroid and hyaluronan administration; and drainage of joint fluid as needed. Tumentia is slight, but she complains of severe pain, particularly in movement, which interferes with her daily life.

Special instructions Regarding her therapy, she does not want to be left with visible scars on account of her occupation. Currently she has no choice but to suspend her work as an actor, which causes her financial concern; she wants to return to her business as soon as possible. Although thus far she has focused on her profession, she has a boyfriend and is now considering future pregnancy. When I discussed your clinical trial with her, she had a positive outlook.

Professor Kazuo Ohmori, MD Orthopaedist Fig. 2. Patient information sheet – patient 2

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INFORMED CONSENT Table 2. Points of attention for informed consent • SITUATION: Informed consent should be conducted not in places which conjure images of medical treatment such as a medical examination room. Thus, white coats should not be worn to avoid prospective participants’ misunderstanding the process for therapy.

• PERCEPTION: It is important to understand what patients know and expect.

• INFORMATION: Information should be delivered without using scientific jargon and technical terms so that it can be understood by prospective participants.

• KNOWLEDGE: Make sure that prospective participants gain enough knowledge throughout the IC process to assess the meaning of becoming research participants and what would happen to them while participating in research.

• EMPATHY: Try to understand prospective research participants’ emotion such as fear and hope. Thus, always pay attention to not only prospective research participants’ words but also to their body language and attitudes and tones.

• SOLUTION: Regardless of obtaining prospective research participants’ agreement or not, make sure that they understand the next procedure after they leave the room, such as making the next appointment for medical treatment or giving them contact address and advising them to consult with their family members. Also, people who conduct informed consent need to be aware that they are responsible for judging participation eligibility in the research of patients.[6]

The workshops began with a lecture detailing six points important for IC: situation, perception, information, knowledge, empathy, and solutions (Table 2).[6] Then mock research protocols were introduced, followed by patients information, and a questionand-answer session. The WPs then explained the research to each mock patient as part of comprehensive IC. The lectures and WPs’ performances were videotaped, and used to review their performances.

Workshop results were then compared to the results obtained in a 2013 iPSC workshop conducted by the Japanese Retinitis Pigmentosa Society (JRPS) that featured a dialogue between retinitis pigmentosa patients and researchers. Correlating workshop results enabled both WP and PRP perspectives to be incorporated into recommendations for improving IC related to stem cell research.

Results

WP performance in the workshops Although WPs performed well overall, they had difficulty with four of the six points deemed necessary for full IC: perception, information, knowledge, and empathy.

Observations regarding WP performance • WPs tended to take too much time explaining what they believed to be important or familiar, such as medical conditions and risks.

• WPs provided the information requested on the consent form, but did so in a scattered order, based on the patients’ questions.

• WPs paused sessions to get answers from the translationalresearch physician for questions they could not anwer, such as medical procedures. The WPs then tried to explain the information to PRPs. • WPs who lacked IC training in the research context found it particularly difficult to explain research processes without using jargon.

• Some WPs failed to notice non-verbal signs such as facial expressions or body language as indications of a patient’s understanding or concerns. For instance, in the case of the woman pressured by her husband, one WP neglected to suggest to the patient that it should be her decision to participate in the trial.

• Some WPs covered information too fast for the PRPs to follow because they focused too much on ‘explaining.’

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Suggestions for improving WP performance • If an elucidator takes too long to explain important aspects of a study it may imply bias regarding the PRP’s ability to participate in the study. For instance, if the elucidator highlights benefits or risk excessively, a PRP might think the elucidator is implying that he or she should or should not participate in the research. Manipulation, coercion, and misrepresentation should be avoided during IC. When explaining the research to PRPs, an elucidator should be careful not to misrepresent the research by overestimating benefits and underestimating risks. Even the order in which items are explained could affect a PRP’s decision. The elucidator should provide information in a neutral manner so that PRPs can make decisions based on their own thoughts and values.

• A well-written consent form should be a ‘roadmap’ ensuring all of the necessary elements are explained during IC. Elucidators should follow the order of the items listed on the consent form. It is during the icebreaking stage that: elucidators can ask PRPs about their reasons for participating in the research; their expectations and concerns; and allow the PRPs to ask questions and express their thoughts and feelings. Elucidators should always organise the meetings in ways that ensure all important information is conveyed.

• WPs tended to think they had to answer every question that the PRPs asked. Some tried to provide medical explanations, which should be left to attending doctors to do. Elucidators should admit their lack of knowledge when asked a question beyond their expertise. The elucidator’s duty is not to provide information he or she is unfamiliar with but to advise PRPs to seek medical information or ask medical doctors for options before deciding to take part in a clinical trial. Elucidators should use the PRPs’ questions to assess their comprehension, educational level, scientific and medical knowledge, and home background, and assess why PRPs want such information. Elucidators must understand that they cannot always adequately address patients’ questions and concerns during the initial recruitment and consent process. They must recognise that IC is a process not a onetime event. They must continually engage PRPs in discussions of the trial design, conduct, and outcomes throughout the research process, especially for studies involving cutting-edge interventions.

• Information should be explained using simple words and easily understood expressions. In our workshop, those involved in stem

INFORMED CONSENT cell research and IC support sometimes found it difficult to explain scientific matters without using technical terms. PRPs often misunderstand that the purpose of a phase-I clinical trial is to evaluate safety, not to find a cure. Elucidators must be able to explain research without causing therapeutic misconceptions and to ensure PRPs’ comprehension in a limited amount of time.

• Elucidators must build their empathy skills and be able to create a rapport that enables PRPs to voice their concerns and ask questions, and enables elucidators to recognise the non-verbal communication signs expressed by PRPs about the information being communicated or other factors that may influence their decision-making.

What information do research volunteers want to know?

In 2013, the Japanese Retinitis Pigmentosa Society (JRPS) held a workshop for regional leaders. After hearing lectures on iPS re­ search, the research process, ethical issues (including therapeutic misconceptions), and participants’ rights and duties, the patients and their families were divided into eight groups of six members to discuss what information they would like when considering participating in a clinical trial. Following is a summary of the information that patients wanted, identified from their comments in the workshop report.[7] • Foreseeable risks and problems, including information on adverse events: ‘[I] would like to know [if it is] possible [for this cancer to] spread all over the body, [and if so, should]...the whole or part [of] the eye...be [removed]?’[7] • Expected burdens and restrictions in daily life, including economic and family burdens: ‘…I would like to know if there is something that [will] restrict my daily life during the follow-up period…. First of all, we would like to get better and contribute to the research. However, I am wondering if I [have to] abstain from alcohol entirely for three years thereafter.’[7] • Physical, psychological, and economic support, including followup care and insurance when an adverse event occurs: ‘We would like to know what kind of care would be provided for each adverse event. We are informed of possible risks in advance, but we would like to know what concrete care [is offered for] each specific adverse event. …We would like to know… the care [offered] if someone’s eyesight was impaired or [he or she] became blind. … We would [also] like to know the medical treatment and/or economic support [offered] for physical symptoms or mental aberrations if they happen.’[7] • Other studies or alternative therapies: One PRP’s concern was whether participating in certain research would limit access to other studies or therapies, or whether participants could easily switch to alternative options if they changed their mind. ‘… we would like to know if other… research [is currently being conducted], not limited to iPS cells, but [interventions] such as artificial retinas and gene therapy. We would like to know of…[issues such as] expected future effects.’[7]

• Previous PRP results and experiences: From a scientific perspective, it is preferable not to share results from previous research participants. However, based on the dialogue and our experiences, patients want such information when they are making their decisions.

‘Second is the information about [previous PRPs’ experiences] in the clinical trial. We would like to know if and when … previous research participants’ results [will be available] …’[7] • What patients can do to prevent adverse events so that they are not disqualified as research participants. ‘… we would like to [know] what we should pay attention to in daily life so as not to cause adverse events [that could] prevent us from [continuing to] participate in the research.’[7] Patients also wanted other information, such as: • Why they were selected as research participants • Expected realistic benefits • Schedules, test items, and restrictions • Treatments and support, if they developed research-unrelated diseases • Restrictions related to pregnancy.

Finally, the patients had requests and suggestions on the research on retinitis pigmentosa: • Suggestions for research designs from a scientific perspective • Requests for consultation services provided by a third party • Requests for thorough cell-quality management, such as con­ tamination prevention • Requests for a mutual-check system of institutional review boards involving representatives from patient groups • The necessity for educational activities conducted by and for the patients themselves.

Overall, the patients were concerned about how participating would impact their daily routines and quality of life, and wanted concrete, precise information before making a decision. Well-written consent forms usually include much of the information desired by patients, although patients often want more informational certainty than can be provided.

Discussion Many studies have been conducted on improving consent forms and readability as well as assessing PRPs’ comprehension, such as the ISSCR guidelines, which propose a written test or an oral quiz during IC.[4] In those cases, the focus is on PRPs’ comprehension and scientific literacy.

However, stem cell research is very technical and, as with much medical research, there is information asymmetry between laypeople and elucidators, particularly where those elucidators are researchers. Hence, relying solely on written consent forms or educating the PRP in initial IC is not enough to achieve IC. Results from the IC workshops discussed in this paper suggest that improving elucidators’ IC competencies is another important and essential element in achieving IC. The competencies required for competent elucidators include not only an ability to explain the research and enhance PRPs’ understanding, but also an ability to judge PRPs’ voluntariness and

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INFORMED CONSENT eligibility to participate in the research. Out of thousands of patients, only a few people will be selected to enrol in an iPSC-FIH clinical trial and to establish iPSC lines, at a cost of tens of thousands of yen per patient.[7] Those selected PRPs carry the hopes of patient groups, researchers, and the country, putting them under implicit and explicit pressures, especially if they want to withdraw from the trial.[7] Thus, securing research participants’ voluntariness and ensuring the right to withdraw from the research is a significant role for elucidators.

Sharing research results with participants is also a challenging issue for elucidators. Various medical examinations are conducted in the process of stem cell research, such as screenings for infectious diseases and cancers, whole genome sequencing, among others. If minors are included as PRPs, a positive result for a sexually transmitted disease may impact the protection of his or her confidentiality as an adolescent, along with parental responsibility. Cancer screenings would also be conducted prior to a PRP being cleared to participate,[7] and whole genome sequencing might be conducted to maintain the quality of cell products for allogenic cell therapy. Obviously, these test results could affect a PRP’s quality of life. In order to competently deal with such diverse issues, elucidators must be able to catch signs of anxiety and concern in PRPs during IC, as expressed verbally and non-verbally by the participants. This requires astute communication skills, not often learned by researchers.

Elucidators also need an ability to establish and maintain partnerships with both PRPs and investigators to ensure long-term safety. Monitoring and ensuring the long-term safety of both active research participants and those who withdraw from the study is also important, due to the essential nature of stem cell research. It may not be possible to remove the implanted cells from the body of either active or inactive patients. An elucidators’ ability to deal appropriately with people in the multiple contexts of stem cell research is another crucial element in protecting research volunteers.

In summary, elucidators need to act not only as information providers assisting PRPs with decision-making, but also as gatekeepers and coordinators. The complexity of their responsibilities will grow as stem cell research advances. Continuous training and education is essential for elucidators to acquire and maintain such complex skill sets and IC competencies in stem cell research. As demonstrated by the workshops, role-playing can be a practical method of transmitting such knowledge and IC competency.

Due to the limitations of our study, additional research is required to confirm whether there are any traits specific to stem cell research in general. Further research is also necessary to confirm what items should be included in elucidators’ IC competency.

Conclusion In our IC workshops, we could not find any specific IC requirements for stem cell research. Well-written consent forms cover most of the information that research volunteers want to know. However, relying only on consent forms is not enough to achieve IC. The IC competency

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of elucidators is another element in protecting research volunteers.

The elucidator’s role requires skill at explaining the research, enhancing PRPs’ understanding, and judging PRPs’ voluntariness and eligibility to participate in the research. The need for ongoing education and training of elucidators is essential to their acquiring and maintaining the skill sets needed for them to fulfil their complex role in obtaining full IC for stem cell research.

Conflict of interest. The IC workshops and the dialogue session mentioned in this paper were funded by the Japan Science and Technology Agency (JST). The authors are involved in ethical support for the Research Center Network for the Realization of Regenerative Medicine, which is organised

by JST. Acknowledgments. Foremost, we would like to express our sincere gratitude to Prof. Sean Philpott-Jones, Director of the Bioethics Program/Director of Research Ethics Program for the Bioethics Program at the Union Graduate College – Icahn School of Medicine at Mount Sinai, for giving practical and valuable instruction during our IC workshops. We also extend our gratitude to Prof. Masayo Takahashi at the RIKEN Center for Developmental Biology for letting us use the consent form from her clinical trial in our workshop. We would also like to thank all participants, Prof. Etsuko Arita at the School of Pharmacy, Kitasato University, and the staff who took part in the 2014 IC training sessions. Last but not least, we would like to express gratitude to Prof.

Robert Congleton of Rider University for his helpful suggestions.

References 1. Reardon S, Cyranoski D. Japan stem cell trial stirs envy. Nature, 16 September 2014. http://www.nature.com/news/japan-stem-cell-trial-stirs-envy-1.15935 (accessed 5 August 2015).

2. Kyodo J. Japanese team first to use iPS cells in bid to restore human sight.

Japan: The Japan Times, 12 September 2014. http://www.japantimes.co.jp/ news/2014/09/12/national/science-health/japanese-ips-based-retinatransplant-a-global-first/#.VeEtRfmvGUk (accessed 5 August 2015) 3. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. United States of America: US Department of Health and Human Services, 1979. http://www. hhs.gov/ohrp/humansubjects/guidance/belmont.html#xinform (accessed 1 June 2015) 4. International Society for Stem Cell Research. ISSCR guidelines for the clinical translation of stem cells.

ISSCR, 2008. h t t p : / / w w w. i s s c r. o r g / d o c s / d e f a u l t - s o u r c e / c l i n - t r a n s - g u i d e l i n e s / isscrglclinicaltrans.pdf (accessed 26 February 2015).

5. Aalto-Setälä K, Conklin BR, Lo B. Obtaining consent for future research with induced pluripotent cells: Opportunities and challenges. PLoS Biology 2009; 7(2):e42. [http://dx.doi.org/10.1371/journal.pbio.1000042] 6. Philpott-Jones S. Lecture. In: Kusunose M, Muto K, Philpott-Jones S. Informed consent in clinical trials using stem cells: Suggestions and points of attention from an informed consent training workshop with stimulated patients [Poster].

ISSCR 2014 Annual Conference, February 2014.

7. Muto K, Takahashi M and Japanese Retinitis Pigmentosa Society (JRPS). Cocreating clinical trials – From a dialogue between patients and researchers [Report in Japanese]. Tokyo: JRPS & Department of Public Policy at the Institute of Medical Science, University of Tokyo, 2014.

RESEARCH

Biobanks and human health research: Balancing progress and protections A Dhai,1 MB ChB, FCOG (SA), LLM, PhD; S Mahomed,2 BCom LLB, LLM; I Sanne,3 MB BCh, FCP (SA), DTM&H Director, Steve Biko Centre for Bioethics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa PhD candidate, Steve Biko Centre for Bioethics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa 3 Managing director; Right to Care. Department of Medicine, Clinical HIV Research Unit, Internal Medicine and Infectious Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

1 2

Corresponding author: Ames Dhai (ames.dhai@wits.ac.za)

Biobanks are repositories that store human biological materials and their associated data. They are rapidly becoming part of national and international networks and give rise to unique ethico-regulatory issues. Whether consent is informed and whether this term should be used when specimens are collected for biobank research is questionable. Where risks occur, they are usually social and relate to identifiability.

Public trust and confidence are important for the success of this type of research. Consensus is growing that governance of biobanks should be harmonised. Controlled specimen and data access agreements are essential. The South African National Health Act (NHA) and its Regulations, that provide the foundation for the legal framework with regard to human tissue and research in South Africa, are silent on the issue of biobanks and the law lags behind while science and technology advance rapidly. The use of biobank assets will lead to significant benefits in human health and should be encouraged while taking account of the associated ethical, legal and social issues and working towards a balance between these two positions.

S Afr J BL 2015;9(2 Suppl 1):55-59. DOI:10.7196/SAJBL.8060

The advent of biobanks in the field of science and technology has seen scientists entering a new age in biotechnology research. General ethical considerations, which apply to health research involving human participants, will apply equally to biobank research. However, in addition, there are unique ethical issues specific to biobank research.

This is because of the nature of biobank research which has evolved to include an intersection of disciplines and networks. While the unique considerations pertaining to genetic research also apply in this context, with biobanks, international collaborations have emerged on a scale not previously seen. Without doubt this type of collaborative research is pivotal to advancing science, health and well-being. Nevertheless, multifaceted ethico-regulatory and social complexities have surfaced, including concerns around individual and group autonomy, informed consent, privacy, confidentiality, secondary use of samples and data over long periods, data sharing, benefit sharing and differing legal requirements across national boundaries.[1] Because biobanks are essential for major advances in health research, a balance is required between the tensions arising from the need for progress towards human health and well-being and ethico-regulatory and social concerns.

In this paper we briefly describe biobanks and the advancement from biobanks to networking and sample and data-sharing. We discuss how the supremacy of informed consent is challenged by this new age research and some of the risks that could occur in the context of biobank research. We highlight the importance of safeguards like specimen and data access agreements and the pivotal role of public trust for the success of this type of research enterprise.

The need for ethics in the governance of biobanks is underscored.

Pertinent international and local ethics and governance documents

are referred to. The legal void in South Africa (SA) with regard to biobank research is also discussed. While the ethico-regulatory issues relating to biobank research in this paper are not exhaustive, we raise what we consider to be the relevant ones.

Biobanks – a brief description Biobanks are repositories that store animal, plant and human specimens.

This paper focuses on biobanks that store human bio­logical materials (HBMs) specifically for research purposes. Biological materials, as defined in the Regulations to the South African National Health Act (NHA)[2] are: ‘material from a human being including DNA, RNA, blastomeres, polar bodies, cultured cells, embryos, gametes, progenitor stem cells, small tissue biopsies and growth factors from the same’.[3] Biobanks are repositories that store not only organised collections of HBMs usually from a large number of donors but also their associated data, including individual health records and information derived from their analysis.[1,4] A well-functioning up-to-date biobank serves to accelerate important advances in health research as it exploits ‘state-of-the-art genetics together with big data sets and individual health records to allow for complex and powerful studies’[4] on an unprecedented scale.

Biobanks collate large numbers of variables and are crucial resources to the understanding of genetic, environmental and lifestyle factors in the aetiology of disease.[4,5] However, in SA, biobanks are typically concerned with the storage of specimens and the crucial bioinformatics capacity of these repositories seem to be very much in their nascent stages.[6] The two broad categories of biobanks are: • those that are involved in large cohort studies where a minimum of tens of thousands of participants is required • those that are disease specific.[4]

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RESEARCH The former are usually referred to as population biobanks and they focus on the promotion of population health.[1,7] There is a paucity of data on the number and types of biobanks operating in the country.

A review documented just over a dozen biobanks in the country and these operate on a smaller scale.[6] Not all of them are specific to research. Those that are involved in human health research are usually smaller collections from research projects within academic institutions.[6] While the National Health Laboratory Services in SA has attempted to establish a population level biobank,[8] this has unfortunately not materialised. The reasons for this are probably multifactorial but in our opinion include bureaucratic hurdles and the lack of a comprehensive ethico-legal framework for biobanks in the country. Although the SA regulatory framework makes provision for tissue banks, these are not biobanks. Tissue banks are defined as ‘an organisation, institution or person that provides or engages in one or more services involving cells and/or tissue from living or deceased individuals for transplantation purposes’.[9] This definition may clearly include a person who provides or engages in these activities. Moreover, the uses of cells and/or tissues are limited to transplantation purposes only. This inelegant definition differs from the internationally recognised definition of a biobank as described above. Notably, the NHA,[2] which provides the foundation and scaffold for the legal framework regarding human tissue and research in SA, is silent on the issue of biobanks. Despite chapter 8 of the NHA being specific to human tissue and chapter 9 to research, none of their regulations provide regulatory direction with regard to biobanks.

Biobanks, networking and data-sharing Biobanks are conventionally defined in terms of their institutional or geographical location. With the emergence of new scientific and computer technology development, HBMs and associated data are rapidly and increasingly becoming part of a national and international network of biobanks. Such networking means that biobanks have the greatest potential as resources for translational research.[10] Data are shared between biobanks when sample sizes are insufficient to produce statistically significant results. Research potential is therefore fully realised.[4] The bigger and more networked the biobank, the greater the power of the research that can be conducted.[10] Certain types of research can only be conducted if there is networking between biobanks, e.g. where rare diseases are studied, a single researcher may not be able to collect an adequate number of samples.

Moreover, some common diseases, like cardiac disease, are now seen to comprise rare disease subsets characterised by specific genetic polymorphisms. Networking also assists in situations where there are social and logistical difficulties with obtaining HBMs.[10] Several categories of biobank networks have evolved over time. These categories are neither exhaustive nor non-mutually exclusive and include:[10] • ‘Storage’ networks – facilities for storage are shared among biobanks to reduce costs and improve quality.

• ‘Bring-and-share’ storage networks – lower fee structures are offered to researchers to encourage sharing of resources with other researchers.

• ‘Catalogue’ networks – maintains a database that can be accessed by external researchers looking for samples for their research.

• ‘Partnership’ networks – costs and efforts in recruitment are shared.

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• ‘Contribution’ networks – relevant specimens are contributed to disease-specific biobanks.

• ‘Expertise’ networks – expertise instead of samples are shared.

South Africa, with its world-class scientists and infrastructure conducive to advancing high-quality, high-tech research, is ideally placed on the continent to integrate these different categories of biobanks and establish networks within the country that would maximise the research potential here. Specimens within these biobanks are from the public and sharing would not only facilitate attaining the desired statistical power and addressing some of the financial and other resource constraint issues, but would be a step in the direction of the common good. Research, conducted with public involvement, is in reality a contract between science and society.

While ethical challenges specific to those of networking and datasharing between biobanks have arisen, these are not insurmountable and should not impede much needed human health research. One of the greatest concerns is that large-scale networking would result in a total disconnect between participants and researchers and as a consequence, researchers would become less accountable to donor interests.[10] Where biobanks have been approved and are subject to oversight by well-functioning, competent research ethics committees (REC), donor interests ought to be taken care of adequately.

Informed consent A key problem, resulting in a bottleneck between conventional established research and biobank research, is the issue of informed consent.[1] Informed consent is both an ethical and legal doctrine forming a necessary component of health research. Ethical challenges in the context of biobank research often focus on the tensions between individual autonomy or respect for persons and utilitarian justice and the common good.[10] We believe that because biobank research involves the contributions of a large number of people, its ethical emphasis should hinge on the utilitarian common good. Due to the nature of biobank research, the focus on individual autonomy and informed consent is seriously challenged. The consent emphasis in classic research ethics is that of individual, first-person consent for sample collection and use for the specific research project that the participant consents to. In addition, the participant consents to storage over a defined period of time. We recommend and encourage researchers to consider storage in biobanks over an indefinite period as such research involves genetic and genomic studies where the intergenerational period is at least 25 years. The consent and sample collection process with biobank research is often separate from the actual research which could be conducted several years later, by a group of different researchers, in different biobanks as compared to when the initial sample collection took place and informed consent was obtained. In addition, the research may involve research questions and methods that could not have been contemplated at the time of sample collection. Specific cell lines could be derived from the samples and these could be duplicated and exchanged through the networks.[1] It is therefore questionable as to whether consent for biobank research is at all informed and whether this term should be used when specimens are collected for biobank research. In addition, classic and biobank consent forms respect participant autonomy to the extent of including a withdrawal clause for the specimens that have been collected.

RESEARCH Clearly, with such extensive networking, sharing of specimens, and transformation of specimens into cell lines, withdrawing of samples will not be as easy as it seems on the consent form and this could be perceived as paying ‘lip-service’ to autonomy. Because of this lack of knowledge of what will happen to the specimens in the future, consent processes must be broad and ‘broad’ consent, ethically and legally is not the same as ‘informed’ consent.

Various models of consent have been offered by ethicists and researchers to address the informed consent difficulties encountered in biobank research. These include re-consent, tiered consent and multi-layered consent with secondary use statements.[1,4,11] However, these could result in consent exhaustion on the part of the participant and increase the financial costs and administrative burdens of the research. Therefore, we advocate obtaining broad consent from participants and assuring them that there would be REC oversight and approval for future research using their samples and data as the most appropriate way forward. This would be in line with the SA Department of Health’s research ethics guidelines which allows for broad consent and defines it as where the ‘donor permits use of biological materials for future studies, subject only to further prior ethics review and approval’.[12] Depending on the category of the biobank, differing degrees of broad consent could be obtained and range from consent to conducting research in a specific sphere in health, or on a specific disease, to unrestricted consent for future health research use as in population biobank studies.[11] International organisations, for example, the Organisation for Economic Cooperation and Development (OECD) advocate this type of broad consent for biobank research.[13] The Draft World Medical Association (WMA) Declaration on Ethical Considerations Regarding Health Databases and Biobanks[14] which has been out for open consultation since March this year, states that individuals must be given the choice to decide whether or not their biological materials will be included in a biobank. The consent process needs to include information on the purpose of the biobank, the nature of the material to be collected, who will have access to the biobank, the biobank’s governance arrangements and how privacy will be protected. It goes on to state that conditional broad consent is acceptable if inter alia all information about future use is provided during the consent process and all use is approved by a dedicated, independent ethics committee. It does not define ‘conditional broad consent’. It also does not take into consideration that because of the evolving nature of biobank research it is not possible to provide all information on future use. It would be interesting to see how the WMA defines broad consent. The Draft Declaration states that blanket or open consent for future use ‘not envisaged at the time of collection is not ethically acceptable’. This, in our opinion, would serve to cripple biobank research as many studies emanating from biobanks involve research questions and methods not envisaged at the time of sample collection.

Risks of biobank research It is important to bear in mind that just as there are societal benefits of biobank research based on the common good, there are societal risks to this type of research. While physical risks of research conducted on samples that have already been collected and stored are rare, social risks need to be safeguarded against.[1] The nature and degree of risk will depend on whether the samples are identifiable and

the type of information that is linked to the sample. Potential risks could extend beyond individual participants to their population groups and the general public. Stigmatisation and discrimination, in particular genetic discrimination, which are frequently group-based, implicating both participants and non-participants, are examples of social risks of biobank research. Moreover, when identifiable samples are used in research, disclosure of sensitive information could result in an invasion of the participant’s privacy.[1] Confidentiality is the main ethical concern regarding identifiability.

It is essential that donors understand the notion of identifiability and the different levels of anonymisation in order to assess the individual consequences of participation.[15] In addition, biobank research implies risk for identifiable groups and communities because anonymity of the individual does not necessarily translate to group anonymity.

Different terms pertaining to identifiability are used for stored tissue in different guidelines and literature. Moreover, the same terms have different meanings in different guidelines and also, at times, within the same guidelines.[15] The latter problem also applies to the SA ethics guidelines. Needless to say, confusion and communication barriers result. A clear indication of levels of identifiability are offered by the following five levels of anonymisation utilised in the European Guidelines:[16]

Anonymous This is appropriate only for archaeological samples. As it is always possible to identify the donor through DNA fingerprinting, where samples contain any trace of DNA, they are not truly anonymous.[16]

Anonymised This term denotes storage of biological material alongside associated information like age, medical treatment, etc. However, all identifying material is removed either irreversibly (unlinked anonymised) or reversibly (linked anonymised). Identification of linked anonymised samples is usually by use of a code which researchers and other users of the samples do not have access to.[16]

Coded Here samples are reversibly linked, anonymised with researchers and users having access to the code.[16]

Identified These are samples with information allowing identification, e.g. name, address, telephone number, etc. Pathology laboratories usually store samples in the identified form.[16] Population databanks, which are mainly longitudinal in nature, would require linked anonymised and coded samples. Fears regarding problems with recruitment because of the potential for identification of the participant must be balanced with utility and the tangible benefits of such a process. Research with potential participants has shown that such fears could be unfounded.[17]

Controlled sample and data access agreements Participants and the public must have assurance that the scientific community will use samples and data from these banks correctly.

Therefore, to ensure controlled access, sample and data access agreements are advocated towards the provision of liberal, but secure

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RESEARCH access of samples and data. While the international guideline on prevention of scientific misconduct (Singapore Statement),[18] and the Draft WMA’s Declaration on Ethical Considerations Regarding Health Databases and Biobanks[14] could have an impact on international laws and practices, they are unclear on how to implement processes to monitor and regulate research integrity.[19] Problems concerning these international documents include:[19] • Implementing national laws in an internationally consistent manner is problematic.

• Immediate, practical solutions for problems that could arise within global genomics projects are often not offered.

• An optimal level of protection is not offered as they are not contractual in nature and their interpretation and enforcement could end up being very costly, unpredictable, lengthy and protracted.

It follows therefore, that establishers of biobanks should have strict controlled-access policies in place which should be approved by a REC. Contractual sample and data access agreements which ensure the proper recognition of all in the research production chain and adequate protections of research participants have been recommended.[19] The HBM recipient has a responsibility similar to that of a trustee or steward in order to ensure protection of the donated tissues. Material Transfer Agreements (MTAs) are an example of such a contractual arrangement. The University of Witwatersrand’s Biobanks Ethics Committee has developed an MTA template which incorporates both ethical principles and legal requirements for use by researchers.[20,21] The need for an MTA prior to samples being transferred is a requirement by the Health Professions Council of South Africa (HPCSA).[22] The SA ethics guidelines only mention that inter-institutional sharing agreements are required to be confirmed in writing. There is no further guidance to researchers on how and at what stage this should be done. The Draft WMA Declaration is silent on the need for contractual specimen and data access agreements.

Public engagement and trust Consultation with the public and ensuring that they clearly understand the functioning of and research conducted by the biobank are some of the key factors towards a biobank’s success.[1,4] Ongoing dialogue between the public, researchers and biobank managers is essential as public support in this context cannot be taken for granted. Moreover, public confidence and trust in biobanks research as being done for the common good must be cultivated. This is essential to maximise participant recruitment and retention of samples. Therefore public support is vital to the development of biobanks.

Two thirds of respondents surveyed in a study that was conducted widely throughout Europe had not heard of biobanks and most respondents, once aware of the concept, were generally supportive.[4] It would be interesting to know what the SA public’s response would be to a similar study. A large-scale survey on the public’s knowledge, understanding and attitude towards biobanks has not been conducted throughout SA as yet. In addition, meaningful conversations on biobanks between the public and researchers are lacking. If SA wants to be at the forefront of this cutting-edge research, commitment is necessary on the part of researchers and scientists to build public trust and confidence in these activities.

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Biobank governance Because of extensive networking between biobanks, there is growing consensus that governance of biobanks should be harmonised, especially if HBMs are to be used broadly.[4,13] In particular, there should be harmonisation in the operating procedures and policies for procurement, collection, storage and transfer of HBMs if the ob­ jec­tive of the biobank, which is that of fostering research, is to be realised. Oversight for this should be provided by the REC. In terms of the OECD guidelines, the establishment, governance, management, operation, access to, use of the biobank and its protocols and processes for research activities, oversight mechanisms, strategies for ensuring long-term sustainability which also addresses the event that funding is terminated or its nature changed, stakeholder consultation (including the general public), and criteria for sampling and participant selection, should be reviewed and approved by an independent REC.[13] The Draft WMA Declaration also requires that an independent REC approves the es­tablish­ment of the biobank.[14] The SA ethics guidelines require that all new repositories have prior REC approval and that the REC should es­ tablish procedures to guide this process and the use of the repository.[12] A weakness of the SA guidelines, which use the terms repository and biobank interchangeably, is that REC oversight with regard to already established biobanks is not mandatory. The Human Research Ethics Committee (Medical) of the University of the Witwatersrand, the oldest REC in the country and among the first to be established in the world (1966),[23] set up its Biobanks Ethics Committee in 2013.[20] The mandate of this committee is inter alia to review applications for the establishment of biobanks and all research pertinent to the use of specimens from the approved biobanks.[21,24] This REC oversight of biobanks was commenced by the REC despite no local directive to do so. Moreover, the REC is guided by the principles of the WMA’s Declaration of Helsinki which does not pronounce on biobank oversight.

Conclusion The value of biobanks in the health research arena must be appreciated by scientists, the public and policymakers alike. The use of biobank assets will lead to benefits in diagnosis and the treatment of numerous diseases. This should be encouraged while considering the associated ethical, legal and social issues and working towards a balance between these two requirements. The importance of public trust and confidence in this equation must not be underestimated.

While advances in science and technology are accelerating, the law in SA unfortunately lags behind. Fortunately though, some institutions have taken their ethics oversight roles seriously and have instituted safeguards, despite the legal hiatus in this regard.

References 1. Dhai A, Mahomed S. Biobank research: Time for discussion and debate. S Afr Med J 2013;103(4):225-227. [http://dx.doi.org/10.7196/samj.6813] 2. Republic of South Africa. The National Health Act No. 61 of 2003. Pretoria: Government Gazette 2004;469:2-94.

3. Republic of South Africa. Regulations relating to the use of Human Biological Materials No R.177. Pretoria: Government Gazette 2012: Section 1.

4. The Parliamentary Office of Science and Technology. Biobanks Postnote 473.

London: Houses of Parliament. 2014. http://researchbriefings.files.parliament.uk/ documents/POST-PN-473/POST-PN-473.pdf (accessed 16 June 2015).

5. European Commission. Biobanks for Europe: A challenge for governance.

Report of the Expert Group on Dealing with Ethical and Regulatory Challenges of International Biobank Research. Brussels: 2012. http://www.coe.int/t/dg3/ healthbioethic/Activities/10_Biobanks/biobanks_for_Europe.pdf (accessed 16 June 2015).

RESEARCH 6. Abayomi A, Christoffels A, Grewal R, Karam LA, et al. Challenges of biobanking in South Africa to facilitate indigenous research in an environment burdened with human immunodeficiency virus, tuberculosis, and emerging noncommunicable diseases. Biopreserv Biobank 2013;11(6):347-354. [http:// dx.doi.org/10.1089/bio.2013.0049] 7. O’Doherty KC, Hawkins AK, Burgess MM. Involving citizens in the ethics of biobank research: Informing institutional policy through structured public deliberation. Soc Sci Med 2102;75(9):1604-1611. [http://dx.doi.org/10.1016/j. socscimed.2012.06.026] 8. Dhai A. Establishing national biobanks in South Africa: The urgent need for an ethico-regulatory framework. S Afr J BL 2013;6(2):38-39. [http://dx.doi. org/10.7196/sajbl.296] 9. Republic of South Africa. Regulations relating to Tissue Banks, No R. 182. Pretoria: Government Gazette 2012: Section 1.

10. Stewart C, Lipworth W, Aparicio L, Fleming J, Kerridge I. The problems of biobanking and the Law of Gifts. In: Goold I, Greasley K, Herring J, Skene L, eds.

Persons, Parts and Property. How Should we Regulate Human Tissue in the 21st Century? Oxford: Hart Publishing UK. 1st ed. 2014;25-38.

11. Gefanus E, Dranseika V, Serepkaite J, et al.Turning residual human biological materials into research collections: playing with consent. J Med Ethics 2012;38(6): 351-355. [http://dx.doi.org/10.1136/medethics-2011-100113] 12. Republic of South Africa. Department of Health. Ethics in Health Research.

Principles, Processes and Structures. Pretoria: Department of Health, 2nd ed. 2015. http://www0.sun.ac.za/research/assets/files/Integrity_and_Ethics/ DoH%202015%20Ethics%20in%20Health%20Research%20-%20Principles,%20 Processes%20and%20Structures%202nd%20Ed.pdf (accessed 14 June 2015).

13. OECD Publishing. OECD Guidelines on Human Biobanks and Genetic Research Databases. Paris: OECD Publishing, 2009. http://www.oecd.org/sti/ biotechnologypolicies/44054609.pdf (accessed 14 May 2015).

14. World Medical Association. WMA declaration on ethical considerations regarding health databases and biobanks. A draft from the work group intended for open consultation after acceptance from the Executive Committee of the WMA. Ferney-Voltaire: World Medical Association, 2015. http://www.wma.net/

en/20activities/10ethics/15hdpublicconsult/2015-Draft-policy-HDB_BB.pdf (accessed 16 June 2015).

15. Cambon-Thomsen A, Rial-Sebbag E, Knoppers BM. Trends in ethical and legal frameworks for the use of human biobanks. Eur Respir J 2007;30(2):373-382. [http://dx.doi.org/10.1183/09031936.00165006] 16. Elger BS, Caplan AL. Consent and anonymization in research involving biobanks.

EMBO Rep 2006;7(7):661-666. [http://dx.doi.org/10.1038/sj.embor.7400740] 17. Rothstein MA. Expanding the ethical analysis of biobanks. J Law Med Ethics 2005;33(1):89-101.

18. Singapore Statement on Research Integrity. 21 – 24 July 2010. http://www. singaporestatement.org/statement.html (accessed 11 January 2013).

19. Joly Y, Zeps N, Knoppers BM. Genomic databases access agreements: Legal validity and possible sanctions. Hum Genet 2011;130(3):441-449. [http://dx.doi. org/10.1007/s00439-011-1044-3] 20. Mahomed S, Behrens K, Slabbert MN, Sanne I. Managing human tissue transfer across national boundaries: An approach from a South African institution.

Developing World Bioethics. South Africa: Wiley Online Library 2015. http:// onlinelibrary.wiley.com/doi/10.1111/dewb.12080/full (accessed 20 June 2015).

21. University of the Witwatersrand Biobanks Ethics committee. Material Transfer Agreement. University of the Witwatersrand, Johannesburg, South Africa, 2015 http://www.wits.ac.za/academic/researchsupport/19112/ethics_application_ forms_guidance_notes_and_policy_documents.html (accessed 12 June 2015).

22. Health Professions Council of South Africa. General Ethical Guidelines for Health Researchers. Pretoria: Health Professions Council of South Africa, 2008. http://www.hpcsa. co.za/Uploads/editor/UserFiles/downloads/conduct_ethics/rules/generic_ethical_rules/ booklet_6_gen_ethical_guidelines_for_researchers.pdf (accessed 19 May 2015).

23. Cleaton-Jones PC. Research Ethics in South Africa: Putting the Mpumalanga Case into Context 240-245. In: Lavery J, Grady C, Wahl ER, Emanuel EJ, eds. Ethical Issues in International Biomedical Research. Oxford: Oxford University Press, 2007.

24. Human Research Ethics Committee (Medical). Ethics application forms, guidance notes and policy documents. Johannesburg: University of the Witwatersrand 2015. http://www.wits.ac.za/academic/researchsupport/19112/ethics_application_ forms_guidance_notes_and_policy_documents.html (accessed June).

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RESEARCH

Benefit sharing in health research S Mahomed,1 BCom, LLB, LLM, PhD candidate; I Sanne,2 MB BCh, FCP, DTM&H Steve Biko Centre for Bioethics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa Managing director; Right to Care, Department of Medicine, Clinical HIV Research Unit, Internal Medicine and Infectious Diseases, University of the Witwatersrand, Johannesburg, South Africa 1 2

Corresponding author: S Mahomed (safia.mahomed@telkomsa.net)

The necessity of benefit sharing may be questioned when research activities are funded by international sources within a developing country.

Benefit sharing is a topic which remains uncertain in the context of genetic research, particularly with regard to how and with whom benefits should be shared. A Material Transfer Agreement (MTA) is one way (and in some instances the only way) in which the transfer of human biological materials is regulated. With biobank research increasing and the historical exploitation of research participants in Africa a reality, it is essential that the transfer of human tissues across national boundaries is regulated with specific regard to the sharing of benefits and the respect and protection of traditional values. This paper will debate the requirement of benefit sharing when research is undertaken; discuss its meaning in the context of genetic research; and outline some South African and international perspectives on the sharing of benefits. While this paper emphasises benefit sharing in the context of genetic research, the principles apply to all human participant research.

S Afr J BL 2015;8(2 Suppl 1):60-64. DOI:10.7196/SAJBL.8012

Benefit sharing is the process or act of sharing in the benefits that derive from research in a manner that is fair and equitable.[1] When considering benefits generated from genetic research, it is unclear how, with whom and by which mechanisms these benefits should be shared, as this area of discussion is somewhat unexplored.[2] In addi­ tion, the necessity for benefit sharing may be resisted specifically when international institutions from the developed world fund re­ search projects within a developing world country. However, the idea of benefit sharing must be balanced with public interests and popu­ lation health.[2,3] The philosophical principle behind the concept of benefit sharing is simple and may be argued as a matter of justice. [4] Those who contribute to scientific research ought to share in its benefits.[4] This is particularly relevant in terms of health research, when the exploitation of South Africa (SA) and the developing world by developed world countries is considered.[2,5] This inequity still exists in certain spheres and needs to be corrected in order to restore equilibrium.[2] A benefit should be received by research participants and/or the institution which provides the samples for the utilisation of their genetic resources and/or resources.[2] With the use of two case studies and relevant national and international laws and guidelines, this paper will debate the requirement of benefit sharing when research is undertaken; discuss its meaning in the context of genetic research; and outline some SA and international perspectives on the sharing of benefits. While this paper emphasises benefit sharing in the context of genetic research, the principles apply to all human participant research.

The importance of benefit sharing when research is undertaken and its meaning in the context of genetic research Reliance on the use of human biobanks for research purposes has increased. In addition, the capacity, size and number of biobanks, has intensified.[2] Human biobanks are capable of storing a vast

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array of genetic data including stem cells for indefinite periods, for uses that may not be established at the time the initial protocol is approved (secondary uses). Ethico-legal complications that storage of data for indefinite periods gives rise to, include (but are not limited to): confidentiality; privacy; ownership; intellectual property; informed consent for secondary uses; and benefit sharing.[2] Justifiably, the complexities that result with the advances challenge local and international ethico-legal frameworks. Of considerable importance and debate is the notion of benefit sharing.

There is argument that participation in scientific research should always be altruistic in nature. This is how access to human genetic resources has been governed historically in prosperous nations.[6] However, exporting this notion into developing countries could lead to the emergence of serious concerns around exploitation. A discussion of two relevant cases below, that involve benefit sharing mechanisms, describe how positive outcomes could be arrived at while engaging in benefit sharing within developing world communities.

The Majengo case study The Majengo sex workers case involved follow-up studies on 850 female sex workers in Kenya. It was thought that they could contribute to the development of a vaccine against HIV. This was part of an ongoing collaborative project by researchers from the universities of Nairobi and Manitoba.[6,7] The women were extremely socio-economically disadvantaged and unable to access quality healthcare in any other way than through their involvement in the clinic which was set up by the research team.[8] The women provided individual informed consent to participate in the ongoing study which utilised their blood, cervical, vaginal and saliva samples.[7,8] The Kenyan regulatory environment includes access to non-human genetic resources and subsequent benefit sharing thereof. However, no regulation or policy existed in respect of human genetic resources.

RESEARCH In 2005, national guidelines for research and development of HIV/ AIDS vaccines[7,9] were developed in specific response to the Majengo case. These guidelines provide a framework for addressing issues of financial compensation for research participants through Material Transfer Agreements (MTAs) and Research and Development Agree­ ments.[7,9] The guideline’s MTA template provides for the ‘fair and equitable sharing of benefits’ derived from the use of biological materials.[10] An argument has been made that benefit sharing agreements could effectively be incorporated into the cooperative research and development agreements. These agreements will then be binding and enforceable in domestic law.[7,8] The Kenyan guidelines further require science and ethics committees in the country to verify the ethical integrity of HIV/AIDS vaccine trial protocols in accordance with internationally accepted ethical guidelines, for example, the ethical considerations in HIV preventative vaccine research of the joint United Nations programme on HIV/AIDS (UNAIDS).[7,9] Guidance Point 10 of the aforementioned document states that: ‘The research protocol should outline the benefits that persons participating in HIV preventative vaccine trials should experience as a result of their participation. Care should be taken so that these are not presented in a way that unduly influences freedom of choice in participation.’[11] While this guidance document is not legally enforceable, it does list what should be considered as minimum benefits for participants in HIV preventative vaccine trials.

The main benefit received by the Majengo participants in the study was healthcare.[7] Prior to the research team establishing a clinic in the slums of Majengo, the participants had no option but to utilise a treatment centre in Nairobi, where services were poor and where healthcare providers discriminated against sex workers.[7,8,12] The sex workers now have non-discriminatory access to healthcare within walking distance. Apart from the direct benefits in terms of healthcare, the clinic also offers a ‘safe haven’[7,8] which enables the women to form new relationships, social networks and develop a sense of solidarity, creating a community environment. Additionally, research publications have brought the participants international exposure which could assist in safeguarding the women’s rights to any benefits that may accrue from ongoing research activities. This case outlines a situation where, as a direct result of the research process, participants benefited both physically and socially by gaining access to much needed healthcare. The research also displayed that, with the right motivation, a disadvantaged and poor population could manage the demands of antiretroviral treatment and achieve the same adherence levels as the general population. This unforeseen outcome is of great significance and benefit to all those affected by HIV/AIDS, independent from the search for a successful preventative vaccine.[7,8]

The San Hoodia case The next scenario does not involve human genetic material; however, it is an example of how one of the first benefit sharing agreements was negotiated in SA in the absence of an enabling domestic legal environment. The San people (among the oldest communities in southern Africa) historically acquired traditional knowledge on the use of Hoodia gordonii, a moist plant found in the Kalahari desert, which the San have customarily consumed to limit hunger on their lengthy, tiring journeys.[13] The San people were at first unaware that the South African Council for Scientific and Industrial Research (CSIR), an arm of

the SA government, were patenting an appetite suppressant which was produced from the Hoodia plant.[13] No credible clinical trials have, to date, documented its safety or efficacy. The CSIR also had plans to commercialise a Hoodia pharmaceutical product without the San people providing their consent, and there was no discussion surrounding the sharing of benefits derived from the subsequent commercialisation.[13] The CSIR and Phytopharm, a pharmaceutical com­pany with a plant extract division, negotiated an exclusive license that transferred rights for research and commercial use of the patent for the development of Hoodia products. Phytopharm then granted licen­ses to Pfizer and the food multinational, Unilever.[13] With the involve­ment of NGOs, in 2003 the San people and the CSIR negotiated one of the first benefit sharing agreements.[13] This provided the San with a share of the royalties derived from the sale of the products containing Hoodia.[13] The benefit sharing agreement received criticism;[13] however, although far from perfect, it is an example for potential future benefit sharing agreements which allow for communities to receive recognition for their traditional knowledge and share in the commercialisation of products based on their knowledge.[13]

South African law and guidelines with regard to the sharing of benefits The Biodiversity Act 10 of 2004

In SA, the Biodiversity Act 10 of 2004[14] is the only legal document that sets out what a ‘benefit’ may constitute for bioprospecting or any other kind of research involving indigenous biological resources. The Act specifically excludes human material from its application, but it does provide for (among others): the sustainable use of indigenous biological resources; and the fair and equitable sharing of benefits arising from bioprospecting or involving indigenous biological res­ ources.[14] Currently, section 1 of the Act defines a benefit to include: ‘both monetary and non-monetary returns’.[14] Therefore, local capacity building would form a benefit as provided for under the Act. Section 81(1)(b) of the Act also: ‘obligates applicants to apply for a permit before any export of the resource is undertaken for research purposes’.[14] In addition, section 82(1)(b) of the Act: ‘protects the interests of any organ of state or community providing or giving access to the indigenous biological resources’. The involvement of the indigenous community is measured before any permit referred to above is issued.[14] With regard to the protection of an indigenous community, the issuing authority will consider the traditional uses of the indigenous biological resources or the knowledge of, or discoveries about the indigenous biological resources before authorising a permit for use of the resources.[14] Section 82(2)(b) of the Act makes it mandatory for the applicant and stakeholder (i.e. a person, organ of state, community or indigenous community) to enter into an MTA which regulates the provision of or access to the resources and a benefit sharing agreement that provides for sharing by the stakeholder in any future benefits that may be derived from the relevant bioprospecting.[15] It is important to note that a permit will not be granted if the preceding two agreements are not entered into by the parties. Section 83 of the Act sets out that the benefit sharing agreement must specify: ‘the type of indigenous biological resources to which the relevant bioprospecting relates; the area or source from which the indigenous biological resources are to be collected or obtained; the quantity of resources to be collected or obtained; any traditional uses of the resources by an indigenous community; and

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RESEARCH the present potential uses of the resources’.[16] The benefit sharing agreement must also name the parties to the agreement; set out the manner and extent to which the resources are to be utilised; set out the manner and extent to which the stakeholder will share in any benefits that may arise; provide for regular review of the agreement; and comply with any other matters that may be prescribed.[17] Section 83(5) of the Act stipulates that the agreement or any amendment thereto will have to be submitted to the Minister for approval and will not take effect unless approved by the Minister. Section 85 of the Act provides for any monies arising from the benefit sharing agreement and MTA and directs that such monies are kept in a bioprospecting trust fund and considered to be trust money managed by the director general who will be accountable for these funds.

As stated above, the Biodiversity Act is the only SA piece of legislation that regulates benefit sharing agreements in terms of providing a definition and outlining what the agreement should contain. Although human material is excluded from the Act, it is a relevant starting point to develop a benefit sharing mechanism of a similar nature, relevant to research involving human material, as has been done recently in the University of the Witwatersrand’s MTA template.

University of the Witwatersrand’s Material Transfer Agreement template During 2014, the University of the Witwatersrand approved an MTA template[1] for human biological materials to be used by its researchers. The definitions section of the template defines benefit sharing as: ‘a process or act of sharing in the benefits that derive from the research in a manner that is fair and equitable’.[1] The template also defines benefits to include among others: ‘the sharing of information, use of research results, royalties, acknowledgement of the provider as the source of the materials, publication rights, transfer of technology or materials, and capacity building’.[1] In an attempt to foster equitable benefit sharing mechanisms, the template provides that the sharing of benefits should be discussed between the parties before any materials are transferred for research purposes.

Ethics in health research: Principles, structures and processes This ethical guideline provides guidance in respect of all forms of research involving animals, human participants, human biological materials and data collected from living or deceased persons, including human embryos, fetuses, fetal tissue, reproductive materials and stem cells.[18] South African research ethics committees are encouraged to adopt these principles in assessing all health research projects.[18] The guideline provides that a risk-benefit analysis should precede carrying out the research and that the likelihood of benefits should outweigh the anticipated risk of harm to participants. The guideline further indicates that there should be a fair balance of risks and benefits among all role-players involved in research, including participants, participating communities and the broader society, in order to express the principle of equality in the research context. In addition, there should be a reasonable likelihood that the population from which participants are drawn, will benefit from the research results, if not immediately, then in the future.[18] It may be argued that ethical guidelines have no legal status.

However, it is important to note that in terms of current legal literature, ethical guidelines are considered as customary

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international law.[19] In order to qualify as customary international law, an ethics guideline must be supported by the consistency and generality of being widely accepted as practice.[19,20] Nevertheless, there is still a large gap between legislative documents with legal status and ethical guidelines.[19,20] Furthermore, it is difficult to compel objectors to the ethical guidelines to comply, which raises concerns surrounding the alleged binding nature of customary international law.[19] Section 39(1)(b) of the Constitution of South Africa instructs that when the Bill of Rights is interpreted, a court, tribunal or forum must consider international law.[21] However, without a legal requirement for the incorporation of benefit sharing agreements into the research process in SA, it is left up to ethics committees to regulate these arrangements on a case-by-case basis. In the absence of clear domestic legislation regarding benefit sharing in the context of human genetic research, a brief description of certain international perspectives relevant to research on human material will follow.

International perspectives on benefit sharing

The Nagoya protocol on access to genetic resources and the fair and equitable sharing of benefits arising from their utilisation The Nagoya protocol on access to genetic resources and the fair and equitable sharing of benefits arising from their utilisation (ABS)[22] is a supplementary agreement to the Convention on Biological Diversity (CBD).[23] South Africa is a signatory to the protocol which provides for the effective implementation of the fair and equitable sharing of benefits arising out of the utilisation of genetic resources.[23] The Protocol was adopted on 29 October 2010 in Nagoya, Japan. Of particular relevance is the reference to human genetic resources in the introduction. Similarly, it is important that: ‘access to affordable treatments by those in need especially in developing countries’ is included in Article 8 of the Protocol, among the special considerations that must be observed when regulating access to genetic resources.[22,23] The Protocol creates incentives to safeguard and sustainably use genetic resources, therefore enhancing the contribution of biodiversity to development and human well-being.[22,23] Among the parties who are required to provide their informed consent and agree to mutual terms are indigenous and local communities that hold genetic resources and/or associated traditional knowledge.[23] With regard to benefit sharing, each party is obligated to take administrative, legislative or policy measures to ensure that benefits are shared fairly and equitably with the party who provides the resources.[24] Capacity building is also emphasised in the Protocol. Parties must participate in capacity development, capacity building, and strengthening of human resources and institutional capacities.[24] Under the Protocol, communities who hold genetic resources and related traditional knowledge are afforded extensive consideration and protection: • Prior informed consent must be provided by these communities for utilisation and access to their resources.

• Benefits must be shared in a fair and equal manner with the communities whose genetic resources or traditional knowledge were utilised.

RESEARCH • Parties shall establish mechanisms to notify users of traditional knowledge about their obligations.

• Parties shall organise community meetings, establish a help desk for communities, and involve communities in the implementation of the Protocol, to increase awareness of genetic resources and traditional knowledge held by communities.

• The Protocol further calls for capacities of communities to be improved, which will enable their effective participation in implementing the objectives of the Protocol.[22-24]

The Declaration on the Human Genome and Human Rights The Declaration on the Human Genome and Human Rights[25] was adopted unanimously and by acclamation at UNESCO’s 29th general conference on 11 November 1997. The following year, the United Nations General Assembly endorsed the Declaration. Article 12(a) of the 1997 Declaration embraces the theory of sharing benefits on the basis of common property and distributive justice. It states that: ‘Benefits from advances in biology, genetics and medicine concerning the human genome, shall be made available to all, with due regard for the dignity and human rights of each individual’. This implies that benefits concerning the human genome may be considered common property and therefore be made available to all.[19,25] Article 19(a) iii indicates that: ‘when international co-operation occurs, developing countries should benefit from the achievements of scientific and technological research in order for their use in favour of economic and social progress to be for the benefit of all’.

Two other international guideline documents, while not specific to genetic research, are also worthy of a brief discussion in this section and follow below.

The Council for International Organisations and Medical Sciences international ethical guidelines for biomedical research involving human subjects The goals of the Council for International Organisations and Medical Sciences (CIOMS) international ethical guidelines for biomedical research involving human subjects[26] are to facilitate and promote international activities in the field of biomedical sciences, in colla­ boration with the United Nations and the World Health Organization (WHO).[26,27] The CIOMS guidelines (developed in conjunction with the WHO) were published in 1993, and updated in 2002. The guide­lines provide broad support, with regard to benefit sharing, and stipulate that a research project should leave low resource countries or communities better off than previously or, at least, not worse off.[26] The guidelines further stipulate that the project should be responsive to health needs and priorities in that any product developed is made reasonably available, and as far as possible leave the population in a better position to obtain effective healthcare and protect its own health.[26] The CIOMS guidelines that deal directly with benefit sharing are: guideline 10, which focuses on post-study access to beneficial interventions and responsiveness to health needs; and guideline 21 which deals with the provision of services that are necessary for making a beneficial intervention and/or product available.[26] Guideline 10 relates to research in populations and communities with limited resources. Before undertaking research in a population or community with limited resources, the sponsor and the investigator must make every effort to ensure that the research is responsive to

the health needs and the priorities of the population or community in which it is to be carried out.[26] Furthermore, every effort must be made to ensure that any intervention or product developed, or knowledge generated, will be made reasonably available for the benefit of that population or community.[26] However, the issue of ‘reasonable availability’ is complex and de­ter­mined on a case-bycase basis.[26] The guidelines provide that in general, if there is good reason to believe that a product developed or knowledge generated by research is unlikely to be reasonably available to, or applied to the benefit of, the population of a proposed host country or community after the conclusion of the research, it is unethical to conduct the research in that country or community.[26]

The Declaration of Helsinki The Declaration of Helsinki[28] was first adopted at the 1964 World Medical Association General Assembly in Helsinki. Its purpose is to provide ethical principles for medical research involving human subjects, including research on identifiable human material and data.[28] Section 19 of the Declaration explains that certain groups or individuals may be considered to be vulnerable and should receive considered protection.[28] Section 20 states that medical research with a vulnerable group is only justified if the research is responsive to the health needs or priorities of the group.[28] Additionally, the group should stand to benefit from the knowledge, practices or interventions that result from the research.[28]

Discussion and conclusion From the above analysis, it is clear that the international guidelines echo a similar message with regard to benefit sharing. In addition, it is apparent that benefit sharing in respect of human material does not imply a monetary transaction only. Any form of advantage, assistance or upliftment to the participant, community and/or providing institution could constitute a benefit and enhance the trust relationship between research participants and institutions, which in turn will foster progress in terms of genetic research.

The international guidelines emphasise the importance of the concept of benefit sharing specifically with regard to developing world countries. With recent developments in the biotechnology arena, it is not implausible that numerous tissue samples may be leaving SA and Africa for genetic research purposes.[29] The Majengo and San cases outline the positive outcomes of benefit sharing arrangements with research participants. The University of the Witwatersrand’s MTA template highlights that benefit sharing should be discussed between parties before tissues are transferred in order to foster equitable benefit sharing arrangements.

Furthermore, international ethical guidelines relevant to human materials shape the importance of benefit sharing as a progressive mechanism for parties to adopt as part of the research process.

According to Slabbert:[30] ‘The challenge for South Africa is to find a benefit-sharing model that tempers (not diminish) commercial interests; that redresses economic imbalance; and that gives research participants a more fair and active role in influencing the sharing of benefits…’[30] The Biodiversity Act provides an excellent starting point to develop a model similar in nature for human biological material. This will enhance confidence and trust in genetic research, which will in turn ensure a sustainable research environment for both research participants and institutions.

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RESEARCH References 1. University of the Witwatersrand Human Research Ethics Committee Medical.

Material Transfer Agreement for Human Biological Materials. Compiled by the Biobanks Ethics Committee. Johannesburg, University of the Witwatersrand, 2014. http://www.wits.ac.za/academic/researchsupport/19112/ethics_application_ forms_guidance_notes_and_policy_documents.html (accessed 23 February 2015).

2. Mahomed S, Behrens K, Slabbert MN, Sanne I. Managing human tissue transfer across national boundaries: An approach from a South African institution.

Developing World Bioethics. 2015 [http://onlinelibrary.wiley.com/doi/10.1111/ dewb.12080/full] 3. Cambon-Thomsen A, Rial-Sebbag E, Knoppers BM. Trends in ethical and legal frameworks for the use of human biobanks. Eur Respir J 2007;30(2):373-382. [http://dx.doi.org/10.1183/09031936.00165006] 4. Arnason G, Schroeder D. Exploring Central Philosophical Concepts in Benefit Sharing: Vulnerability, Exploitation and Undue Inducement. In: Schroeder D, Lucas JC. Benefit Sharing: From Biodiversity to Human Genetics. New York: Springer.2013;9-31.

5. Chennells RS. Equitable access to human biological resources in developing countries: Benefit sharing without undue inducement (in press). United Kingdom: School of Health: University of Central Lancashire, PhD thesis, 2014.

6. Lucas JC, Schroeder D, Arnason G, et al. Donating Human Samples: Who Benefits?

Cases from Iceland, Kenya and Indonesia. In: Schroeder D, Lucas JC. Benefit Sharing: From Biodiversity to Human Genetics. New York: Springer 2013;95-128.

7. Lucas JC, Schroeder D, Chennells R, et al. Sharing Traditional Knowledge: Who benefits? Cases from India, Nigeria, Mexico and South Africa. In: Schroeder D, Lucas JC. Benefit Sharing: From Biodiversity to Human Genetics. New York: Springer 2013;65-93.

8. Andanda P, Cook Lucas J. Majengo HIV/AIDS Research Case. A Report for GenBenefit, 2007. https://www.uclan.ac.uk/research/explore/projects/assets/ cpe_genbenefit_nairobi_case.pdf (accessed 24 February 2015).

9. Kenyan Ministry of Health. Kenyan Ministry of Health National Guidelines 2005. https://www.globalgiving.org/pfil/1108/projdoc.pdf (accessed 21 February 2015).

10. Ministry of Health. National Kenyan Guidelines for Research and Development of HIV/AIDS Vaccines. Appendix 5: Biological Material Transfer Agreement. Kenya: Ministry of Health 2005. https://www.globalgiving.org/pfil/1108/projdoc.pdf (accessed 21 February 2015).

11. United Nations. Ethical Considerations in HIV preventative vaccine research.

UNAIDS guidance document. Joint United Nations Programme on HIV/AIDS. Geneva: United Nations 2000. http://data.unaids.org/publications/IRC-pub01/ JC072-EthicalCons_en.pdf (accessed 22 February 2015).

12. Bandewar SVS, Kimani J, Lavery JV. The origins of a research community in the Majengo observational cohort study, Nairobi, Kenya. BMC Public Health 2010;10:630. [http://dx.doi.org/10.1186/1471-2458-10-630] 13. Tellez VM. Recognising the traditional knowledge of the San people: The Hoodia case of benefit sharing. http://www.ipngos.org/NGO%20Briefings/Hoodia%20 case%20of%20benefit%20sharing.pdf (accessed 22 February 2015).

14. Republic of South Africa. Biodiversity Act 10. Government Gazette 2004.

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15. Republic of South Africa. Biodiversity Act 10, Section 82(2)(b)(i)&(ii). Government Gazette 2004.

16. Republic of South Africa. Biodiversity Act 10, Section 83(1)(b). Government Gazette 2004.

17. Republic of South Africa. Biodiversity Act 10, Section 83(1)(c) – (g). Government Gazette 2004.

18. Republic of South Africa. Department of Health Ethics in health research: Principles, Structures and Processes. 2nd ed. Pretoria: Department of Health, 2015.

19. Andanda P, Schroeder D, Chaturvedi S, et al. Legal Frameworks for Benefit Sharing: From Biodiversity to Human Genomics. In: Schroeder D, Lucas JC. Benefit Sharing: From Biodiversity to Human Genetics. New York: Springer 2013;333- 364.

20. Brownlie I. Principles of Public International Law. New York: Oxford University Press, 2003.

21. Republic of South Africa. Constitution of the Republic of South Africa Act 108.

Government Gazette 1996.

22. Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilisation. Secretariat of the Convention on Biological Diversity, 2011 https://www.cbd.int/abs/doc/protocol/nagoyaprotocol-en.pdf (accessed 12 February 2015).

23. The Convention on Biological Diversity 1992 http://www.cbd.int/abs/about/ (accessed 13 February 2015).

24. Kamau EC, Fedder B, Winter G. The Nagoya Protocol on access to genetic resources and benefit sharing: What is new and what are the implications for provider and user countries and the scientific community? Law, Environment and Development Journal 2010; 6(3):246-262.

25. United Nations Educational, Scientific and Cultural Organisation. Universal Declaration on the Human Genome and Human Rights. Geneva: United Nations, 1997. http://www.unesco.org/new/en/social-and-human-sciences/themes/ bioethics/human-genome-and-human-rights/ (accessed 15 February 2015).

26. The Council for International Organisations of Medical Sciences (CIOMS) in collaboration with the World Health Organization (WHO). International Ethical Guidelines for Biomedical Research involving Human Subjects. Geneva: World Health Organization, 2002. http://www.cioms.ch/publications/layout_ guide2002.pdf (accessed 14 February 2015).

27. Macrae DJ. The Council for International Organisations and Medical Sciences (CIOMS) guidelines on ethics of clinical trials. Proc Am Thorac Soc 2007;4(2):176-179.

28. World Medical Association. WMA Declaration of Helsinki – Ethical Principles for Medical Research involving Human Subjects. Helsinki: World Medical Association, 1964. http://www.wma.net/en/30publications/10policies/b3/ (accessed 20 March 2015).

29. Sathar A, Dhai A, Van der Linde S. Collaborative international research: Ethical and regulatory issues pertaining to human biological materials at a South African institutional research ethics committee. Dev World Bioeth 2014;14(3):150-157. [http://dx.doi.org/10.1111/dewb.12018] 30. Slabbert MN. The legal regulation of access and benefit-sharing of human genetic resources in South Africa. J Contemp Roman-Dutch Law 2011;74:605.