A Summary of the Recommendations from the National Forum on Xenotransplantation

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Introduction

In November 1997, a group of experts from a broad range of backgrounds got together in a National Forum to talk about xenotransplantation, a term usually meant to describe the transfer of organs or tissues from animals into humans for medical purposes. The Forum participants included doctors, ethicists, veterinarians, animal rights leaders, transplant recipients, public health officials, provincial representatives and federal regulatory authorities. Xenotransplantation is not a currently recognized medical practice in Canada or in other industrialized countries. However, some countries have allowed limited and controlled "clinical trials," in which medical scientists are trying out some promising procedures on informed patient volunteers. To date, no proposals for clinical trials involving xenografts have been received or approved by Health Canada. Health Canada recognizes that although xenotransplantation has not yet been conducted in Canada, the people of Canada have a right to understand and debate the matter. That way, Canada will be able to develop good public policy to protect both humans and animals, in case xenotransplantation ever proves to be a safe, effective, and acceptable technology.

As a first step in this public consultation process, the Therapeutic Products Programme of Health Canada sponsored the National Forum on Xenotransplantation, to give people with experience in the field a chance to discuss what they felt were the key ethical, medical and regulatory issues in the xenotransplantation debate. This publication summarizes their discussions.

Xenotransplantation means transplants of living cells, tissues and organs between unrelated species. It can refer to grafts from one type of animal to another. However, in this document, it is used principally for animal-to-human transplants. Xenografts are the live cells, tissues, and organs used in xenotransplant procedures.

The main reason for medical scientists to explore the potential of xeno-transplantation is to find alternatives for human organ and tissue transplants. Although many human transplant operations are highly successful, there is always a severe shortage of suitable organs and tissues from human donors.

What about pig heart valves? It's true that medical science already uses animal parts for various therapeutic reasons, such as replacement heart valves. However, these therapeutic products are not functional, living tissue. This distinguishes them from the viable organs used in xenotransplantation.

Some Issues for People

The Need for Public Involvement

We can't know yet whether researchers will ever make xenotransplantation a common procedure, but we do know that Canadians have to start thinking about the issues today. The Forum noted that decision-makers need to hear from the public at all stages of the process. Some of the most important questions for discussion are:

• what are the potential risks of the technology to patients and society at large?
• what are the potential benefits of xenotransplantation for sick or dying patients?
• how do the benefits stack up against the risks and ethical issues?

The Need for Scientific Research

There are many medical obstacles to xenotransplantation. Even in human-to-human transplants, there is a tendency for the patient's immune system to reject the foreign organ or tissue. That is why transplant recipients need to take drugs to suppress their immune systems, often for the rest of their lives. But because a graft from an animal is considerably more "foreign" to the human body, the risk of rejection is even higher. This inherent "biological incompatibility" may be the single biggest challenge for xenotransplantation researchers.

Other risks have both a personal and a societal dimension. For example, there is the possibility that a tissue or organ graft from an animal could carry an infection that we don't know how to detect or treat in humans. Not only would this pose a danger to the patient, but the infection could also spread to the patient's family and beyond.

However, the Forum noted that such "xenozoonotic diseases" had not been seen in the limited clinical trials conducted up until that time.

The Forum participants recognized that:

• a range of questions on immunological and infectious disease risks should be addressed in preclinical trials before proceeding with clinical trials;
• limited clinical trials under controlled circumstances would be required at some point in the future if successful xenotransplantation practices are to be developed.

In particular, the Forum recommended that:

• for xenotransplantation to be considered as an acceptable medical procedure, Canadians ought to weigh the social, ethical, and financial implications against the potential benefits.
• scientists continue to study the infectious disease risks associated with xenotransplantation. Investigations should increase our knowledge of the mechanisms by which these foreign germs (or xenozoonotic agents) cause disease, and possibly lead to laboratory screening tests that could detect their presence in transplant tissues.
• researchers find ways to control the risk of immune system rejection of tissue grafts. This would include an exploration of alternate ways of implanting tissues (for example in special protective capsules) to reduce the chances of rejection.

Biological incompatibility refers to the differences in tissues between species that makes xenotransplantation extremely difficult. This incompatibility is least severe between humans and other primates, and increases as species become more different. But even though monkeys are theoretically good sources for transplant tissue, it is their biological similarity to us that raises all kinds of ethical dilemmas.

Zoonoses are animal diseases which can be transmitted to humans under natural conditions. Both animals and humans are affected by zoonoses, which include rabies, brucellosis, and mad cow disease (Creutzfeldt-Jakob disease in humans). Xenozoonoses are zoonoses specifically transmitted by xenotransplantation.

Preclinical trials include all laboratory research short of tests on humans. Clinical trials involve tests on informed and consenting volunteers. Health Canada will permit clinical trials only if they are safe and will prove something medically worthwhile. Proposed trials also require approval from independent ethics boards at the hospital or research facility where the work is to proceed.

Patient Ethics

The risk of xenozoonotic disease transmission means that patients receiving transplanted animal tissue would need to be closely monitored for the rest of their lives. Information on their medical condition would have to be fed into databanks so that doctors and scientists could learn from each transplant procedure. Moreover, since xenozoonotic diseases could spread among humans, the patient's close contacts would need to be monitored as well.

The Forum concluded that such a large-scale information-gathering process has a number of ethical consequences. Among them:

• patients may need to be selected for clinical trials based on the likelihood that they would consent to lifelong monitoring of their health status, as well as an autopsy after their death;
• comprehensive monitoring could limit a patient's autonomy and privacy;
• the risk of xenozoonotic disease transmission means the patient's close contacts may need to be monitored too; informed consent to participate in clinical trials would therefore have to be obtained from patients as well as close contacts.

Some Issues on the use of Animals

The National Forum said that the use of animals for food or in medical research does not automatically justify their use for xenotransplantation. It should be up to the Canadian public to decide whether animals ought to be used as sources of donor organs and tissues for humans.

Whatever Canadians decide, the Forum argued that animals should only be considered for xenotransplantation if other therapies are not available. Moreover, medical science should endeavour to minimize the number of animals used for this purpose by:

• improving the existing system for collecting and distributing donated human organs;
• co-ordinating human surgeries to ensure that the greatest possible number of tissues and organs from a single animal are put to good use;
• establishing an international registry to avoid duplication in the creation of "transgenic," or genetically altered, animal strains. (Some animals are altered to carry a human protein that can blunt the human immune system's tendency to reject a xenotransplant.)

Apart from the biological concerns, there are complicated ethical and practical considerations involved in choosing a suitable animal source for organs and tissues. Monkeys are closest to us biologically. However, because they are highly social creatures, it is difficult to raise them in the sterile and isolated surroundings necessary for tissues that are to be used in xenotransplantation. For this and other reasons, some researchers are suggesting that pigs may be a better source of organs and tissues for xenotransplantation.

Standards of Care

The Forum noted that there are certain special requirements if animals are to be raised as sources for xenotransplants. For example:

• the facilities housing these animals must have a high level of "biosecurity." This refers to the precautions that are taken to reduce the risk of disease transmission between animals, from animals to humans, and from humans to animals.
• animals must be carefully monitored for the development of diseases
• animals must be raised in a manner that respects their social and behavioural needs.

The Forum recommended the creation of a central registry to keep track of issues related to the care and use of animals for xenotransplantation. It also called for oversight by independent experts on a proposed National Animal Care Committee.

Regulatory and Management Issues

The National Forum envisaged a structure in which everyone involved in xenotransplantation from the technicians raising the animals to the doctors implanting the organs would apply the best methods and information within a lawful and ethical context. Here are some of the proposed elements of such a structure:

National Registries

Whether for clinical trials or the active practice of xenotransplantation, national databases would have to be created to manage all of the relevant information. For example, while protecting patient confidentiality, information should be collected on all aspects of the transplant technology as it affects both animals and people, as well as any long-term effects on patients and their close contacts. Such registries would have to be easy to access and update, and should link to databases in transplant hospitals and donor animal facilities in Canada and around the world.

Federal Regulation

The Forum proposed that Health Canada regulate xenografts just like any other therapeutic products under the Food and Drugs Act. This means that clinical trials involving xenografts would first have to be approved by the federal regulator. In addition, the regulator would apply a "standards-based" approach, which would give rules governing xenotransplantation the force of law.

Standards-based regulation means that every practice associated with xenotransplantation would have to meet or exceed clearly defined standards under federal law. For example, standards could define how animals should be raised, how tissues must be handled, how surgeons are to be accredited and what information must be registered in a databank. An advantage of this approach is that it is easier to update standards than to keep amending regulations.

Ethical Review

The Forum felt that hospitals or other research establishments that wanted to conduct clinical trials on xenotransplantation would have to obtain approval from their internal Research Ethics Boards, as is done for all types of clinical trial proposals. This approval would be in addition to the approval of the federal regulator mentioned above. Among other things, the Boards would have to ensure that patients and their contacts were fully informed and counselled before giving their consent to participate in clinical trials.

Advisory Bodies

The Forum called for the creation of a National Advisory Board on Xenotransplantation -- a panel of independent experts that would advise both the regulator and the local Research Ethics Boards. A proposed National Animal Care Committee (please see page 4) would also provide guidance on the ethical use and care of animals.

Have Your Say

The National Forum emphasized the importance of public involvement at all stages of discussion on the future of xenotransplantation technology. The Therapeutic Products Programme of Health Canada therefore wants to hear from you. Please share your views with us in any of the following ways:

By mail:

Policy Division
Bureau of Policy and Coordination
Therapeutic Products Programme
1600 Scott Street, 2nd Floor, Tower B
P.L. 3102C5
Ottawa, Ontario
K1A 1B6

By fax: (613) 941-6458

By e-mail: btox_stu@hc-sc.gc.ca

For further information, please visit our website

Other resources available on the website and from Health Canada include:

• The complete report of the National Forum on Xenotransplantation
• Fact sheet on xenotransplantation