Introduction: old and new regulatory issues
Starting with the early 1990s the main critical issues in xenotransplantation have been well identified and explored as far as ethical and regulatory aspects are concerned. The normative approach to xenotransplantation has traditionally focused on the balancing of risks and benefits provided by xenotransplants, especially as far as the expected benefits for patients suffering from life-threatening conditions may favor acceptance of this experimental therapy. A number of issues have been highlighted as the major subjects in the debate. These include (but are not limited to) the strict requirements for the patient's informed consent; the peculiar features of informed consent in this setting (namely the potential behavioral restrictions for the patient, her/his close contacts and the healthcare personnel); the potential risks of infections and epidemics by the transmission of xenogeneic pathogens; the social acceptance of xenotransplantation as a viable biotechnology and a potential solution to human organ shortage; the use of animals, especially the use of nonhuman primates as recipients in preclinical trials [1•,2].
However, with a certain area of xenotransplantation – namely swine pancreatic islets – coming very close to clinical applications, normative aspects need to be thoroughly specified and adapted to new contexts and concrete situations. The advancements in the field of pancreatic islets and their potential to become widely available, safe and effective therapies require dedicated reflection. Safety remains the core issue in order to proceed with clinical trials, but there is a need to rethink it with other regulatory aspects of xenotransplants in a global dimension.
Pancreatic islets: towards clinical trials?
As has been widely recognized in the scientific community, in the last few years the transplanted pancreatic islets have taken the lead in the development of xenotransplantation . Although the field has been in development since the early 1990s , the recent results and data published in this sector are more than encouraging. The studies performed by several centers and groups [5,6] showed the functioning of pig islets in nonhuman primates for weeks or months, maintaining the diabetic recipient in an insulin-independent state for a long period. Although some preclinical trials used wild-type islets, other experiments transplanted islets that had been obtained from transgenic pigs; the promising development of alginate-encapsulated pig islets addresses the possibility of avoiding immunosuppression .
All these successful applications raised the need for a consensus document that expressed a common position by the scientific community with regards to clinical trial protocols [8,9•].
The development of well and effective pig islet xenotransplant protocols could make islet xenotransplantation a widely available treatment option for diabetes. Despite the still existing need for further studies regarding the long-term efficacy and safety of the transplantation of porcine islets in nonhuman primates, the majority of scientists involved are inclined to think that this will approach be the first clinical application of xenotransplants. In fact, through gene modification and cloning, xenogeneic islet transplantation might be improved to the point at which it becomes an immunologically superior alternative to the transplantation of allogeneic islets , also because, at least in perspective, this treatment may become widely available and affordable.
Some main regulatory problems, namely informed consent, the selection of patients, and the potential risk of porcine endogenous retrovirus (PERV) transmission that have been discussed at a more general and theoretical level, now need to be adjusted to the context of pancreatic islets.
Informed consent and the criteria for patient selection require a slightly different approach when dealing with diabetes and diabetic patients. In fact, as the main literature on informed consent has taken into account primarily patients with extremely severe health conditions (patients close to death), the reality to focus on now is a disease that affects a significant fraction of the world's population with a variety of available treatments.
According to the authors who are exploring this new situation, at least as to the selection criteria for initial trials candidates, an agreement exists about considering the new therapy as a life-saving procedure [10•], which diabetic patients with hypoglycemia unawareness and a history of severe hypoglycemia could be eligible [11•].
However, it is clear that these criteria will evolve through time and some major problems that involve informed consent may be solved. Patients involved in such trials will more likely be considered as ‘expert patients’ , a concept (based on a programme launched by the UK Department of Health) that stresses the importance of making patients who are affected by chronic conditions directly engaged, aware and responsible in the management of their health (as most diabetic patients already are). Also, xenogeneic cell-therapies have the potential for stronger acceptance from the public, being perceived more as a pharmaceutical product than as an animal organ (as recent research about the perception of xenotransplants have shown ).
The risk of PERV transmission still remains a concern in islet xenotransplants. Therefore, appropriate regulatory oversight, adequate life-long monitoring [11•], and the archiving of tissue from both donor and recipient for a long period of time (50 years for FDA, 30 years in the EU) should be applied to clinical trials. Safety aspects need to be weighed with respect to individual rights and privacy, though islets encapsulation may have the potential to reduce the risk of infections .
Regulating xenocells: the different approaches of the United States and the European Union
Cell-based therapies and tissue-engineering products have been developed separately from xenotransplants both from the scientific and regulatory points of view [15,16]. However, recent developments in pancreatic islets have given rise to closer connections between the two domains and called for joint attention from the respective scientific experts and regulatory authorities [17•]. Several cell therapies and tissue-engineered products use cells of human, as well as of animal, origins, which makes the regulatory issues between the two fields necessarily overlapping and intertwining [18,19•].
However, there are differences between the United States and European Union regulatory strategies towards cell-based products. In the United States, the FDA Center for Biologics Evaluation and Research (CBER) and, specifically, the Office of Cellular, Tissue and Gene Therapies (OCTGT)) oversees cellular products and tissues that meet the regulatory criteria for biologic products, which have been regulated since the 1990s. Allogeneic pancreatic islets are regulated as biological products subject to licensing under Section 351 of the Public Health Service Act (PHS Act). 42 USC 262. They also meet the definition of ‘drug’ in the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 USC 321(g), and are thus subject to certain requirements of the FD&C Act . FDA considers somatic cell therapy in the United States to be ‘experimental’, rather than a standard medical practice. Therefore, cellular products cannot be used clinically without an Investigational New Drug (IND) application or an approved Biologics License Application (BLA) issued to licensed products.
Regarding xenogeneic pancreatic islets, although OCGT is competent for both allogeneic and xenogeneic cells, these products are regulated by different provisions. In fact, as has been again recently reaffirmed in a 2008 FDA Guidance , whenever a product contains cells of animal origin (also if a feeder cell line of animal origin is used to propagate human cells), the final product falls within the definition of a xenotransplantation product, and the Guidance for Industry of 2003  and the PHS Guideline of 2001  will, therefore, apply .
In the European Union, at the end of 2007, Regulation 1394/07 was approved on so-called advanced therapy medicinal products (ATMP), namely gene therapy, somatic cells therapy and tissue-engineered products. This regulation established provisions for placing viable cell-based and tissue-based products for human use in the market . Somatic cell therapy and tissue-engineered products may contain cells of human and/or animal origin, whereas, in tissue-engineered products, allogeneic and xenogeneic cells are associated with medical devices ex vivo or in vivo (e.g. microcapsules, intrinsic matrix scaffolds, biodegradable or not). The main rationale for the legal document (that entered into force on December 30, 2008) is the establishment of a centralized authorization procedure for all AMTP through an interdisciplinary expert committee, the Committee for Advanced Therapies (CAT), within the European Medicines Agency (EMEA), as the main accountable body in defining and evaluating advanced therapies. Due to the special safety and quality precautions, the regulation authorizes stricter requirements on risk management, including the complete traceability of donors, recipients, tissues and products in order to prevent potentially negative public health events.
Therefore, in the United States two distinct regulatory provisions apply to human and to animal-based products. In contrast, in the European Union, Regulation 1394/07 covers all ATMP products. A single template for the Revised Clinical Trial Application (CTA) form for ATMP, which sets the standards for clinical trials with allogeneic and xenogeneic cells investigational medicinal products, is under preparation within the European Commission . In 2003, EMEA established the points to consider for xenogeneic cell therapy medicinal products , which should be revised and updated by the end of 2008 when Regulation 1394/07 enters into force in all European Union Member States .
A renewed regulatory focus on nonhuman primates
Although the need for preclinical trials is still, or even more, strong in approaching the acceptable level of safety and efficacy for clinical trials, the use of nonhuman primates for experimentation has been widely discussed in the last 2 years. There is a particular concern and uncertainty about the future of the acceptability from the general public of using nonhuman primates in medical research. This is primarily because of their evolutionary proximity to human beings and, consequently, because of their relevant mental, psychological and social characteristics [27•].
A renewed concern for the issue was revealed by the Weatherhall Report on the use of nonhuman primates in research, published at the end of 2006 . In reviewing the areas in which nonhuman primate research is focused, the report concluded that there is a strong scientific case for the carefully regulated use of nonhuman primates, although the recognition of this necessity comes with several restrictions. In fact, the United Kingdom expert group accepted a moral case for careful, well monitored and meticulously regulated nonhuman primate research – provided it is of a high quality and has the potential to benefit mankind, and if it is the only way of solving important scientific or medical questions. The experimental use of nonhuman primates should be allowed only when there are no other means to address clearly defined questions of particular biological or medical importance. Also, information about evolving research technology in the interested fields, with particular respect to the need for nonhuman primates, should be regularly collated and disseminated to funding bodies, ethics committees and regulatory agencies. Moreover, scientific journal articles should include details of animal welfare and steps taken to ameliorate suffering in all published papers that involve nonhuman primate research. Finally, also in this case, further efforts are needed to improve interactions between regulatory bodies at national and international levels and between regulatory bodies and the scientific community.
Despite these carefully formulated recommendations, in 2007 a group of Members of the European Parliament urged the Commission and the Council of Minister to use the revision process of Directive 86/609/EC as an opportunity to: make ending the use of apes and wild-caught monkeys in scientific experiments an urgent priority; and establish a timetable for replacing the use of all primates in scientific experiments with alternatives .
Later in the same year a formal petition signed and sent by a number of European citizens asked European Union institutions to stop experimentation on nonhuman primates. The European Commission replied , set up a public consultation and, in November 2008, submitted to the Parliament a new proposal for a Directive on the protection of animals used for scientific purposes [31,32].
This renewed social and regulatory focus on nonhuman primates  does not concern only the European countries, but also Japan, Australia and New Zealand have moved forward in defining stronger criteria of protection. In approaching the threshold of clinical trials in islet xenotransplantation, the need for research in nonhuman primates has become even more important. As the Weatherhall report also recognizes, there is a general tendency to accept and justify animal research when directly applied towards a well defined medical need.
National and international regulatory frameworks: a leading role for WHO
Not only do the majority of countries around the world still lack adequate regulation, both for xenotransplants and cell-based and tissue-based products, but also the regulatory gaps among different legal systems as to public health protection and the uneven enforcement of fundamental human rights between developed and developing countries, leave the worldwide normative landscape looking quite inadequate to cope safely with the new therapies . Although the health issues and threats originating from globalization, primarily the potential spread of infections, are complex and largely unaddressed, an increasing number of clinical trials with animal cells therapies are submitted to health authorities in various countries. Recently, the problems connected to private and commercial funding in xenotransplantation trials have become more extreme as the lack of regulatory measures may attract research teams and industries willing to conduct experimental procedures that would hardly be accepted in countries with stronger regulation . In Malaysia, the case of a cell-factory – whose activities have been recently stopped by the government – advertised human and animal stem cell transplants as ‘worldwide available treatments for incurable and untreatable diseases’. This case is just one striking example of this challenging situation .
The WHO has been very active since the late nineties  in exploring the problematic issues associated with xenotransplants and in raising Member States' awareness of both the potential benefits and risks involved in it through the publication of several reports [38–40] and the launch of a public consultation.
In 2004, WHO emphasized the role of national regulatory authorities, urging Member States ‘to allow xenogeneic transplantation only when effective national regulatory control and surveillance mechanisms overseen by national health authorities are in place’ (WHA57.18) .
However, despite the WHO warning, in 2006 one major national regulatory body in the United Kingdom, UKXIRA (the United Kingdom Xenotransplantation Regulatory Authority) was discontinued, whereas other nation states have only established local or regional authorities. The case of UKXIRA, established in 1997 to advise the US Secretary of State on specific issues such as safety, shows how the risk of inadequate regulation may also be found in countries that have addressed xenotransplantation scientific and normative issues since the very beginning of research. The flaws of local systems of control may consist in ‘a return to the cyclic performance of experimental xenotransplants’ [42•] and, in general, in unsafe conditions in public health, with the potential challenge of pandemics. A regulation at the national level – and possibly at the international one – is the appropriate and necessary response.
In 2007 and 2008, several initiatives have been undertaken at the international level to stop organ trafficking and transplants tourism [43,44]. The risks involved in xenotourism may result in even wider public health threats.
The discovery of a new arenavirus in allotransplanted patients  and the renewed concern in xenotransplants about the potential adaptation of PERVs to humans [46,47] – which in a worst-case scenario, might result in the emergence of a new viral disease – should be a constant reminder of safety aspects, even though other studies have shown more reassuring results . In an interesting analysis that highlights the growing global burden caused by emerging infectious diseases (EIDs) between 1940 and 2004, Jones et al.[49••] showed that EID events are dominated by zoonoses (60.3%) , the majority of which (71.8%) originates in wild animals (for example, severe acute respiratory virus and Ebola virus), and are increasing significantly over time.
Both the need for safety and the promising applications of xenoislets have revived WHO's attention regarding the need for guidelines for clinical trials, and appropriate controlling mechanisms for such trials. In November 2008, a Global Consultation on Regulatory Requirements for Xenotransplantation was held in Changsha (China), co-organized by WHO, the Chinese Ministry of Health, the University of central-south China, and the International Xenotransplantation Association . Among WHO's interests in strengthening its attention and normative role in xenotransplantation is the need for a global system overseeing xenotransplant regulation, the need for national competent authorities, the exchange of information, the prevention of unregulated ‘xenotourism’, and the granting of support for states and the coordination of xenotransplantation vigilance, surveillance and response to suspected infections.
The construction of a stronger regulatory framework committed to both safety and efficacy – and not just to safety – for clinical trials may prevent the performance of loosely regulated trials, the exploitation of vulnerable populations, and the improvement of safety and security. The need to connect local, national and supranational regulatory bodies and to strengthen the effectiveness of the international normative level should be an essential part of this regulatory framework .
Although high profile international institutions such as WHO may appear to be more relevant as soft law regulators, the connection between xenotransplants and the need to prevent epidemics around the world may lead to a strengthening of the role of WHO in this field.
The International Health Regulations (IHR) were initially adopted by the Health Assembly in 1969 with the limited aim of covering six ‘quarantinable diseases’, but through time they underwent substantial changes due to the need to cope with the emergence or reemergence of international disease threats and other public health risks. The present purpose of IHR (2005) is ‘to prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks, and which avoid unnecessary interference with international traffic and trade’ . The successful implementation of the WHO International Health Regulations (IHR), which is binding for all the countries who committed to meeting the new requirements of the regulations, may contribute significantly to enhancing national, regional and global public health security. A possible harmonization of current national policies against infectious diseases does not depend only on the availability of scientific expertise and economic resources for public health, but it is also a function of heterogeneous ‘public health cultures’ – namely of approaches to communicable disease control that are more community oriented or more liberal and rights based [54••].
The new achievements in the domain of xenotransplanted pancreatic cells and the potential proximity of safe and effective clinical trials are transforming regulatory issues, calling for national and international normative oversight to take place.
It is noteworthy to see the increasing will of international actors (leading countries and organizations) to unite and harmonize their efforts towards the establishment of a ‘common good’ on this sensitive subject. This support would not only promote research for this rapidly evolving subject, but also ensure that proper and necessary safety measures are adequately agreed upon and shared. Therefore, under the guidance and support of WHO, xenotransplantation should definitively be regulated internationally.
We would like to acknowledge all members of the project XENOME. This work is supported in part by the European Commission funded project LSHB-CT-2006-037377.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 214–215).
1• Shapiro RS. Future issues in transplantation ethics: ethical and legal controversies in xenotransplantation, stem cell, and cloning research. Transplant Rev 2008; 22:210–214. A concise illustration of the ethical and legal issues that surround xenotransplantation, stem cell and cloning research, as potential approaches for alleviating allograft shortage.
2 Vanderpool HY. Informed consent in clinical research. Xenotransplantation 2007; 14:353–354.
3 Groth CG. Looking back, heading forward. Xenotransplantation 2008; 15:1–2.
4 Groth CG, Korsgren O, Tibell A, et al
. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 1994; 344:1402–1404.
5 Hering BJ, Wijkstrom M, Graham ML, et al
. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates
. Nat Med 2006; 12:301–304.
6 Cardona K, Korbutt GS, Milas Z, et al
. Long-term survival of neonatal porcine islets in nonhuman primates
by targeting constimulation pathways. Nat Med 2006; 12:304–306.
7 Gianello P, Dufrane D. Encapsulation of pig islets by alginate matrix to correct streptozotocin-induced diabetes in primates without immunosuppression. Joint meeting of the International Xenotransplantation Association (IXA), the International Pancreas and Islet Transplant Association (IPITA), and the Cell Transplant Society (CTS). Minneapolis, Minnesota, USA. Xenotransplantation 2007; 14:441.
8 Groth CG, Korsgren O. Proceedings of ‘Pig-to-Man Islet Transplant Summit’ held at the Nobel Forum, Stockholm, June 4–5, 2007. Xenotransplantation 2008; 15:77–78.
9• A Consensus Document Based on the Pig-to-Man Islet. Proceedings of Pig-to-Man Islet Transplant Summit. Transplant Summit Held in Stockholm, June 4–5, 2007. Xenotransplantation 2008; 15:79. The recent agreement of the xenotransplantation scientific community on the main scientific and ethical criteria for clinical trials
with swine pancreatic islets
10• Eckhoff DE. Selection of candidates for islet xenotransplantation. Xenotransplantation 2008; 15:102–103. Framing the criteria for clinical trial participants selection and for informed consent in the context of pancreatic islets
11• Schuurman H-J. Regulatory aspects of pig-to-human islet transplantation. Xenotransplantation 2008; 15:116–120. Rethinking xenotransplantation regulatory requirements in the context of pancreatic islets
13 Rubaltelli E, Burra P, Sartorato V, et al
. Strengthening acceptance for xenotransplantation: the case of attraction effect. Xenotransplantation 2008; 15:159–163.
14 European Medicines Agency (EMEA), Points to consider on xenogeneic cell therapy medicinal products (EMEA/CPMP/1199/02), London, 17 December 2003.
15 Farrugia A. When do tissues and cells become products? Regulatory oversight of emerging biological therapies. Cell Tissue Bank 2006; 7:325–335.
16 Wonnacott K. Update on regulatory issues in pancreatic islet transplantation. Am J Transplant 2005; 12:600.
17• Sanzenbacher R, Dwenger A, Schuessler-Lenz M, et al
. European regulation tackles tissue engineering. Letter to the editor. Nat Biotech 2007; 25:1089–1091. An overview of the recent European regulation on advanced therapy medicinal products.
18 Schmidt H. Impact of the German tissue act on xenotransplantation. Xenotransplantation 2008; 15:298.
19• Straßburger J. The regulation of xenotransplantation in Germany and in the European Union. Xenotransplantation 2008; 15:299–300. A summary of all relevant legal documents dealing with xenotransplantation in Germany and the European Union.
20 Guidance for FDA reviewers and sponsors: content and review of chemistry, manufacturing, and control (CMC) information for human somatic cell therapy investigational new drug applications (INDs) - 4/9/2008 http://www.fda.gov/cber/gdlns/cmcsomcell.htm
23 Bloom ET. National policies for xenotransplantation in the USA. Xenotransplantation 2007; 14:345–346.
24 Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004
26 European Medicines Agency (EMEA), Committee for Human Medicinal Products (CHMP), Concept Paper on the Revision of the Points to Consider on Xenogeneic Cell Therapy Medicinal Products (EMEA/CHMP/165085/2007), London 2007.
27• Francescotti R (Guest Editor). Special issue on Animal Minds. The Journal of Ethics 2007; 11:237–335. A special issue that focuses on animals' mental capabilities as grounds for their ethical worthiness.
29 European Parliament, Written Declaration, pursuant to Rule 116 of the Rules of Procedure by Jens Holm, Rebecca Harms, John Bowis, Martine Roure and Mojca Drčar Murko on primates in scientific experiments, 23.4.2007, 40/2007.
31 Commission of the European Communities, Proposal for a Directive of the European Parliament and of the Council on the protection of animals used for scientific purposes (presented by the Commission), Brussels, 5.11.2008, COM(2008) 543 final, 2008/0211 (COD).
33 Quigley M. Nonhuman primates
: the appropriate subjects of biomedical research? J Med Ethics 2007; 33:655–658.
34 Cozzi E, Sykes M. Xenotransplantation: current standards for clinical trials
. Xenotransplantation 2007; 14:347.
35 Sykes M. 2007 IXA Presidential Address. Progress toward an ideal source animal: opportunities and challenges in a changing world. Xenotransplantation 2008; 15:7–13.
37 Noël L. The proactive role of the WHO. Xenotransplantation 2007; 14:348–349.
38 WHO, Xenotransplantation: guidance on infectious disease prevention and management, World Health Organization: emerging and other communicable diseases, surveillance and control, WHO/EMC/ZOO/98.1.
39 OECD/WHO consultation on xenotransplantation surveillance: summary World Health Organization Department of Communicable Disease Surveillance and Response, WHO/CDS/CSR/EPH/2001.1.
40 WHO Guidance on xenogeneic infection/disease, surveillance and response: a strategy for international cooperation and coordination, World Health Organization, Department of Communicable Disease Surveillance and Response, WHO/CDS/CSR/EPH/2001.2.
42• McLean S, Williamson L. The demise of UKXIRA and the regulation of solid organ xenotransplantation in the UK. J Med Ethics 2007; 33:373–375. An analysis of flaws and risks connected to the weakening of the regulation of xenotransplants in the United Kingdom.
43 Budiani-Saberi DA, Delmonico FL. Organ trafficking and transplant tourism. A commentary on the global realities. Am J Transplant 2008; 8:925–929.
44 The Declaration of Istanbul on Organ Trafficking and Transplant Tourism, International Summit on Transplant Tourism and Organ Trafficking Convened by the Transplantation Society and International Society of Nephrology in Istanbul, Turkey, April 30–May 2, 2008. Transplantation 2008; 86:1013–1018.
45 Palacios G, Druce J, Du L, et al
. A new arenavirus in a cluster of fatal transplant-associated diseases. N Engl J Med 2008; 358:991–998.
46 Denner J. Recombinant porcine endogenous retroviruses (PERV-A/C): a new risk for xenotransplantation? Arch Virol 2008; 153:1421–1426.
47 Louz D, Bergmans HE, Loos BP, Hoeben RC. Reappraisal of biosafety risks posed by PERVs in xenotransplantation. Rev Med Virol 2008; 18:53–65.
48 Garkavenko O, Dieckhoff B, Wynyard S, et al
. Absence of transmission of potentially xenotic viruses in a prospective pig to primate islet xenotransplantation study. J Med Virol 2008; 80:2046–2052.
49•• Jones KE, Patel NG, Levy MA, et al
. Global trends in emerging infectious diseases. Nature 2008; 451:990–993. An insightful analysis of a database of 335 emerging infectious diseases events in order to allow a deeper understanding of global temporal and spatial patterns of infectious diseases.
50 Denner J. Emerging infectious diseases and xenotransplantation. Xenotransplantation 2008; 15:305–1305.
51 Global Consultation on Regulatory Requirements for Xenotransplantation - Changsha, China. Co-organized with the Chinese Ministry of Health, the University of central-south China, and the International Xenotransplantation Association. http://www.who.int/transplantation/events/en/index.html
52 Tallacchini M. Defining an appropriate ethical, social and regulatory framework for clinical xenotransplantation. Curr Opin Organ Transplant 2008; 13:159–164.
54•• Gainotti S, Moran N, Petrini C, Shickle D. Ethical models underpinning responses to threats to public health: a comparison of approaches to communicable disease control in Europe. Bioethics 2008; 22:466–476. A thoughtful overview of the different policies and public health cultures around communicable disease control that exist in a select number of countries across Europe.