Clinical Trials of
Xenotransplantation:
Waiver of the Right
to Withdraw from a
Clinical Trial Should
Be Required
Monique A. Spillman and
Robert M. Sade
X
enotransplantation is defined as “any procedure that involves the transplantation,
implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a
nonhuman animal source, or (b) human body fluids,
cells, tissues or organs that have had ex vivo contact
with live nonhuman animal cells, tissues, or organs.”1
Xenotransplantation has been viewed by desperate
patients and their surgeons as a solution to the problem of the paucity of human organs available for transplantation. Foes of xenotransplantation argue that the
use of animal organs degrades the human race and
should be avoided.2
In this paper, we briefly review the cultural context
of xenotransplantation and explore the infectious disease risk of xenotransplantation. The United States
Code of Federal Regulations requires life-long surveillance of a xenotransplantation recipient due to the
largely unknown risk of novel infectious disease transmitted across species, known as xenogeneic infectious
disease. We argue that despite being in the interest of
protecting the public health, the imposition of lifelong surveillance requirements on xenotransplant
recipients effectively abrogates the right to withdraw
from a clinical trial after the transplantation has taken
place. Moreover, we argue that a waiver of the right
to withdraw should be made explicit in the interest of
full disclosure, out of respect for the research subject’s
right of self-determination. While the waiver of the
right to withdraw from a clinical trial appears to be
unique to xenotransplantation, a similar waiver of the
right to withdraw from clinical treatment can be found
in the Ulysses contracts employed in psychiatry. We
also argue that the concept of Ulysses contracts may
be instrumental in providing ethical justification for
requiring xenotransplantation clinical trial subjects to
waive their right to withdraw from the trial.
Cultural Context of Xenotransplantation
In ancient Greek mythology, the chimera was a fearsome beast with the head and forelegs of a lion, the
body of a goat, and a serpent for a tail. Other hybrids
in the mythologies of antiquity include the centaur,
Monique A. Spillman, M.D., Ph.D., is an Assistant Professor in the Department of Obstetrics and Gynecology at the
University of Colorado at Denver and Health Sciences Center.
Robert M. Sade, M.D., is Professor of Cardiothoracic Surgery and Director of the Institute of Human Values in Health
Care at the Medical University of South Carolina in Charleston, South Carolina. He serves as Chair of the Ethics Committee of the American Association for Thoracic Surgery, the
Standards and Ethics Committee of the Society of Thoracic
Surgeons, and the American Medical Association’s Council on
Ethical and Judicial Affairs. He also is the Ethics Editor of the
Annals of Thoracic Surgery.
100 years of transplantation • summer 2007
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SYMPOSIUM
gorgon, satyr, and sphinx. In more recent times, tales
of hybrid entities, including half-man, half-beast creatures, have been depicted in mythology and literature.
Often invoked to frighten recalcitrant children, tales
of vampires and werewolves abound in fairy tales,
but more benign chimeras, such as mermen and mermaids, are also common. Xenotransplantation recipients today are chimeras, with a mixture of human
and animal tissues, along with their viruses, retroviruses, and other potentially infective agents. Even if
the transplanted tissues were removed, the recipient
would still be a chimera due to the exposure to animal
cells and admixture of animal fluids and their biological contents.
Despite the primal fear invoked by chimeras, the
modern scientific era has seen the creation of human
chimeras in xenograft experiments. Peter Gorer was
the first to coin the term “xenotransplantation” in
1961, referring to transplantations between a donor
and recipient of two different species.3 Eight cases of
heart xenografts have been reported, with chimpanzee,
baboon, sheep, and pig hearts.4 The most famous xenotransplanted heart was the “Baby Fae” case. Baby Fae
was a premature newborn with hypoplastic left heart
syndrome, who received a baboon heart transplanted
by Dr. Leonard Bailey at Loma Linda Medical Center.5 Living for twenty days after transplantation, she
was the longest survivor of a xenotransplanted heart.
After her death, controversy surrounded the decision
to transplant a baboon heart into the newborn, rather
than to wait for a compatible human donor. Questions
were also raised regarding the informed consent of
the parents.6 The controversy surrounding the Baby
Fae case prompted an almost complete moratorium
on xenotransplantation in the United States.
Some recipients of xenotransplanted organs died
from overwhelming infections. 7 None of the cases
of overwhelming infection was proven to be from a
novel infectious agent; however, a group of distinguished scientists grew increasingly concerned with
the possibility of infection from xenotransplants and
published their call for a moratorium in the journal
Nature.8
Infectious Disease Risks
Zoonoses, or diseases transmitted between humans
and animals under natural conditions,9 are exemplified
by the human immunodeficiency virus (HIV), which is
thought to have crossed into the human population by
mutation of a related simian immunodeficiency virus
(SIV) acquired from wild primates in Africa.10 Similarly, the hemorrhagic Ebola virus has leaped from primate to man, causing high death tolls during sporadic
epidemics.11
266
Zoonotic infections making the transition from animals to man depend upon stochastic chance and favorable environments. Could a similar event transpire
in a closely controlled research setting, or by unsuspected contamination of a therapeutic drug or device?
For example, in a disturbing laboratory accident, the
Ebola-related Marburg virus was introduced from a
primate to man.12 Fortunately, the infection was contained before a widespread epidemic started.
In another incident, many thousands of people were
exposed to Salk polio vaccine contaminated with SV40
virus.13 The transmission of SV40 raised fears of iatrogenic leukemia; however, those fears were not realized. Similarly, the yellow fever vaccine given to World
War II troops was contaminated with avian leukosis
virus (ALV).14 Again, no demonstrable disease due to
human exposure to ALV was found.
Xenotransplantation poses the risk of introduction
of new or mutated infectious agents into the human
population. Xenogeneic infectious agents are “infectious agents that become capable of infecting humans
due to the unique facilitating circumstances of xenotransplantation; includes zoonotic infectious agents.”15
According to the Institute of Medicine, “although the
degree of risk cannot be quantified, it is unequivocally
greater than zero.”16
The infectious risks of xenotransplantation can be
categorized by risk-reduction strategies employed to
minimize the potential for infection. The most likely
candidate species for xenotransplantation is the pig,
for a variety of reasons, including ready availability,
well-known anatomy and physiology, and compatibility with human anatomy in terms of both size and
morphology. Diseases that are known to be carried
by donor animals, such as Toxoplasma gondii17 commonly found in pigs, can be controlled by careful animal husbandry and herd health surveillance. Creation
of a sterile colony of pigs is feasible and may be necessary. Other diseases can be eliminated by vaccination
of the colony or by screening donor animals. Animal
handlers may also need to be screened to decrease the
risk of transmission of human infections to the herd
(e.g., Mycoplasma tuberculosis).18 Further risk reduction can be accomplished by quarantine of a donor
animal as well as observation for infection for a period
of time before the transplant is accomplished. Despite
all of these precautions, however, the specter of xenogeneic infections still hovers due to retroviruses that
may integrate into the host’s genome and subsequently
reactivate to shed new virus.
The porcine endogenous retrovirus (PERV), for
example, is a retrovirus that is capable of infecting
human cells. It is far from a theoretical risk, as transmission of PERV from swine cells in culture to humanjournal of law, medicine & ethics
Spillman and Sade
cultured cells has been demonstrated.19 In addition,
PERV transmission has been demonstrated in vivo
from pig cells transplanted in immunocompromised
mice.20 However, a study of long-term survivors of porcine pancreatic islet cell transplantation revealed no
xenogeneic infections from PERV after nine years.21
Both the scientific community and the lay public
are keenly aware of the consequences arising from
an unknown infection with a long latency period. We
learned from the HIV/AIDS crisis that an infection
could go unrecognized until an epidemic was already
educate his/her close contacts regarding the possibility of xenogeneic infections….”25 The document also
requires education in safe sexual practices and other
behavior modifications to decrease the risk of spreading the disease. In a related document from the FDA,
the education of xenotransplantation recipients also
includes a clause that requires monitoring by the clinical trial sponsors of the recipient’s “close contacts.”
Close contacts are defined as those persons with whom
xenotransplantation recipients repeatedly engage in
activities that could result in intimate exchange of
body fluids.26 Xenotransplant recipients may be required to disclose the
If xenotransplantation is to take place at all,
names of their sexual partners so that
contact tracing can be performed by
the public health must be protected from the
the clinical trial.
possibility of xenogeneic infectious diseases
The PHS Guideline also clearly
with epidemic potential. There is precedent for
states that the informed consent process for xenotransplant recipients
mandatory public health interventions in the face
must emphasize “...the importance
of potential transmission of infectious disease.
of complying with long-term or lifelong surveillance necessitating rouin progress. By the time HIV/AIDS was recognized,
tine physical evaluations and the archiving of tissue
the American blood supply was tainted, and many
and/or body fluid specimens for public health purthousands of persons were infected. The public health
poses even if the experiment fails and the xenotransrisk of an epidemic from a novel infectious agent
plantation product is rejected or removed.”27 Later, the
acquired through a xenotransplant must be balanced
PHS clarifies to clinical trial sponsors that “post-xenoagainst the needs of an individual awaiting a life-savtransplantation clinical and laboratory surveillance of
ing organ.
xenotransplantation product recipients is critical,” and
that the post-xenotransplantation surveillance is lifeLife-Long Surveillance of Xenotransplant
long.28 Clinical trial sponsors are required to store all
Recipients
surveillance specimens for at least 50 years after the
The lessons learned from the HIV/AIDS epidemic
transplantation is performed.29
have made the guardians of the nation’s blood supply
A specific schedule for surveillance is outlined.
more vigilant. Eligibility criteria for blood donations
Xenotransplant recipients are required to submit to
are more rigid than ever. In the same vein, the Food
sampling prior to the transplantation, and also at two
and Drug Administration (FDA) Center for Biologweeks, four weeks, and six weeks after transplantaics Evaluation and Research has called for a life-long
tion.30 Other samples are required at one month and
moratorium on the donation of blood and blood prodsix months post-transplant, then annually for the first
ucts by xenotransplant recipients.22 In addition, health
two years.31 Subsequent surveillance is mandated every
care workers who have had a percutaneous exposure
five years for the rest of the recipient’s life.32 The FDA
to the body fluids of a xenotransplant recipient must
echoes the life-long surveillance requirement that the
also “indefinitely defer” blood donations.23
passive screening program “should extend for the life
The mandate to defer blood donation may not seem
of the recipient.”33
an onerous burden on a xenotransplant recipient in
Even after death, the trial sponsor is required to
the name of public health protection. However, the
acquire samples at autopsy. The section on informed
scope of the requirements and restrictions for xenoconsent emphasizes “…the importance of a complete
transplant recipients contained in the Public Health
autopsy upon the death of the xenotransplantation
Service (PHS) Guideline on Infectious Disease Issues
product recipient, even if the xenotransplantation
in Xenotransplantation24 is much wider.
product was previously rejected or removed. Advance
The PHS Guideline on “Informed Consent and
discussion with the recipient and his/her family conPatient Education Processes” state that the “informed
cerning the need to conduct an autopsy is also encourconsent process should include a documented proceaged in order to ensure that the recipient’s intent
dure to inform the recipient of the responsibility to
is known to all relevant parties.”34 The underlying
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assumption is that the xenotransplant recipient will
consent to the autopsy, but no alternative options are
discussed.
Despite new privacy protections under the Health
Insurance Portability and Accountability Act, the
government requires that xenotransplant recipients
consent to “long term need for access by the appropriate public health agencies to the recipient’s medical
records.”35 The FDA goes a bit further in stating that
the informed consent document “…should inform the
patient that all data, including data collected during
the follow-up period, could be made available to PHS
agencies.”36 In addition to the records that the clinical
trial sponsors are required to maintain, a pilot project
for a national xenotransplantation database is mandated in the PHS Guideline.37 This would link together
the recipient’s medical information, the xenotransplantation clinical trial data, and the source animal’s
information from all clinical trial centers.
Waiver of the Right to Withdraw from a
Clinical Trial?
Arthur Caplan stated, “It is of special importance
given the high odds of failure in the initial phase of
xenografting on human subjects that procedures be in
place for ending the experiment if the subject wishes
to withdraw from the research.”38 But, how does the
experiment end? Does it end when the organ fails or
is removed? Does it end because the recipient decides
that it is over, withdraws from the trial, and walks
away? Does it end when the sponsor is no longer interested and wishes to terminate support? How can public health officials control the late, long-term risks of
xenogeneic infections if the experiment ends?
The PHS Guideline and related FDA documents
clearly intend that xenotransplant recipients will be
subject to life-long surveillance, even if the xenotransplant is removed or fails. This effectively abrogates
the patient’s right to withdraw from a clinical trial, as
articulated by the Belmont Report,39 the Declaration
of Helsinki,40 and other national and international
ethical guidelines for research on human subjects.
Ironically, the PHS Guideline also states:
In the process of obtaining and documenting
informed consent, the sponsor and investigators should comply with all applicable regulatory
requirement(s) (e.g., Title 45 Code of Federal
Regulations Part 46;…) and should adhere to…the
ethical principles derived from the Belmont Report
of the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral
Research….41
268
The Ethics Committee of the International Xenotransplantation Association highlighted the tension
between life-long surveillance requirements and
human-subject research ethics in this way: “Asking a subject to agree to life-long monitoring effectively denies him or her the right to withdraw from
the study at any time, a fundamental right which is
delineated in the Declaration of Helsinki and the U.S.
Code of Federal Regulations.”42 Regrettably, this position paper offered no guidance to resolve the conflict
between public health needs for life-long surveillance
and the individual’s right to withdraw from the clinical trial.
Informed consent and its corollary, informed
refusal, flow from the ethical principle of respect for
persons. This fundamental principle also underlies
the right of a research subject to withdraw from a
clinical trial at any time. In xenotransplantation, the
ethical underpinnings of clinical research appear to
conflict with public health needs. Two questions arise
from this conflict. Can the patient ever waive the right
to withdraw from a clinical trial – i.e., is that right
inalienable? To protect the public health, can the federal government effectively abrogate the patient’s right
to withdraw from the clinical trial, ignoring de facto a
portion of their own regulations, and fail to inform the
patient of the loss of this right?
Patrik Florencio and Erik Ramanathan have argued
that “…the recipient’s right to self-determination continues after the initial consent has been given and
treatment has begun. Recipients could withdraw their
consent, written or otherwise, at any time. The right
to withdraw consent exists even in the context of lifesustaining interventions.”43
Writing from the perspective of contract law regarding the surveillance safeguards, they continue that
“…compulsory compliance with the safeguards would
require the relinquishment of certain civil liberties that
likely could not be contracted away as a matter of public policy or human rights.”44 Despite this assertion,
however, the question of whether the right to withdraw can or cannot be contracted away in the context
of a threat to public health has not been addressed or
settled as a point of law.
The federal guidelines beg the question of what
will happen if a xenograft recipient refuses to comply
with the required periodic testing when the guidelines
stipulate long-term surveillance of xenograft recipients while concomitantly failing explicitly to mandate
compliance with that surveillance. If xenotransplantation is to take place at all, the public health must be
protected from the possibility of xenogeneic infectious
diseases with epidemic potential. There is precedent
for mandatory public health interventions in the face
journal of law, medicine & ethics
Spillman and Sade
of potential transmission of infectious disease, which
Mandatory long-term clinical surveillance after
is discussed in the next section. Therefore, requiring
xenotransplantation probably meets these requirethat volunteers for xenotransplantation comply with
ments: (1) the very purpose of the clinical trial is to
long-term surveillance seems reasonable. Thus, the
assess rigorously the risks and benefits of the xenoinformed consent documents for xenotransplantation
transplant in a scientifically valid manner; (2) if the
trials should explicitly state that the recipient waives
body fluid surveillance schedules were incorporated
the right to withdraw from the study, once the transinto routine post-transplantation clinical evaluation,
plant has taken place, because of the requirement of
they would not create an undue burden on the subject,
long-term or life-long surveillance
for xenogeneic infections. Clearly disWhile the typical clinical trial informed consent
closing to the recipient the need for
surveillance and eliciting the waiver
is designed to explain the personal risk and
of the right to withdraw may be the
benefits of the trial, it falls short of addressing the
best way to honor the ethical princibalance between societal and personal risks in
ple of respect for persons.
Once the subject has waived the
xenotransplantation. An interesting idea is found
right to withdraw from the clinical
in the concept of Ulysses contracts.
trial, what mechanism is available
to ensure that the subject will actually comply with long-term surveillance? What will
nor do other measures that decrease infection transhappen to the recipient or the recipient’s family if he
mission, including safe sex, which are proven public
or she fails to comply? As David Cooper and Robert
health interventions; (3) subjects are neither quaranLanza have commented, “Like other human beings,
tined nor isolated; (4) because they are not confined,
some patients will agree to a commitment when dessubjects who wish to breach their contractual waiver of
perate, yet renege on it once they are no longer under
the right to withdraw have ready access to the judicial
the gun.”45
system; and (5) it is hard to imagine a less restrictive
means to protect the public health than periodic testEnforcement of Xenotransplantation
ing of body fluids.
Surveillance
Florencio and Ramanathan argue that convenWhen a patient undergoes a therapeutic procedure,
tional public health law is insufficient for the surveilwe do not ordinarily think of follow-up testing as
lance risks of xenotransplantation in the absence of
being required; the patient should comply, but if he
an actual epidemic caused by xenogeneic infection.48
chooses not to, we do not force him to be tested. XenoThey further state that the emergency public health
transplantation is different form ordinary procedures,
powers provided under the Model State Emergency
because the risk is not solely borne by the patient, but
Health Powers would also be impotent against a
also by others. Xenotransplantation is associated with
future possibility of a xenogeneic disease.49 They may
public health issues that do not exist after other therabe correct in their assessment, but we are not arguing
peutic procedures.
for the applicability of public health law to xenotransThe current state of common law and contract law
plantation; rather, we are merely arguing that the
in the United States may not be sufficient to address
legal logic that undergirds those laws can also justify
xenotransplantation surveillance concerns.46 Public
mandatory long-term surveillance of xenotransplant
health law may under some circumstances authorize
recipients.
quarantine of persons who have had high-risk infecA possible legal mechanism for compelling xenotious disease exposures or who are, in fact, infected.
transplant recipients to submit to surveillance is
The U.S. Supreme Court ruled that suspension of indithrough specific federal legislation mandating complividual rights in the interest of public health requires
ance. Florencio and Ramanathan suggest that monthat the following conditions be met: (1) the risks
etary fines could be attached to the failure to composed are subject to rigorous scientific assessment;
ply with submission of blood or fluid samples or for
(2) the restrictions are targeted to avoid undue burfailure to keep clinical surveillance appointments.50
dens; (3) a safe and healthy environment is provided
In order to effectively implement the abrogation of
for those placed under restriction; (4) procedural due
the right to withdraw from the clinical trial, Florencio
process is protected; and (5) the least restrictive posand Ramanathan argue that legislation must explicitly
sible means of achieving the desired public health outstate that the right to withdraw does not apply to xenocomes is used.47
transplant recipients.51
100 years of transplantation • summer 2007
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SYMPOSIUM
Ulysses Contracts
then the contract would be enforced, regardless of the
Imposing the weight of federal legislation to enforce
recipient’s wishes at that time.
PHS and FDA xenotransplantation surveillance
Some have argued that psychiatric Ulysses contracts
guidelines may provide a legal solution to the conflict
are strongly paternalistic, substituting the judgment
between public health and research ethics, but it would
of a physician and the courts for the individual’s decinot address the ethical issues of respect for persons,
sion-making authority. However, Ryan Spellecy makes
self-determination, and informed consent. While the
a compelling argument that Ulysses contracts are a
typical clinical trial informed consent is designed to
tolerable form of weak paternalism. He invokes a planexplain the personal risk and benefits of the trial, it
ning theory of practical reasoning, in which patients
falls short of addressing the balance between societal
make a decision that ultimately overrides a later wish
and personal risks in xenotransplantation. A new parthat stems from an error in reasoning.54
adigm of informed consent is needed for xenotransThe International Xenotransplantation Association
plantation. An interesting idea is found in the concept
insists that “…it will be essential to select research subof Ulysses contracts.
jects who appear capable of fully understanding the
In psychiatry, Ulysses contracts are an advance
potential impact of their behavior on the rest of society,
directive from a patient to a treating psychiatrist. The
and who seem genuinely motivated to minimize these
contracts derive their eponym from the mythology of
risks.”55 The xenotransplantation Ulysses contract
Ulysses. The Sirens were creatures
who had the body of a bird and the
As an advance directive to minimize akrasia or
head or upper body of a woman.
They made irresistible music,
to avoid errors in reasoning, the Ulysses contract
enchanting the sailors on passing
for xenotransplantation would satisfy the ethical
ships so they would approach the
imperative of respect for persons and the corollaries
island, thus ensuring that their
ships would crash on the rocks
of self-determination and informed consent.
around the island and sink, killing all aboard. Ulysses wanted to
hear the music of the Sirens, but didn’t want to lose
would appear to fulfill this purpose by forthrightly
his ship. Therefore, before passing the Sirens, Ulysses
revealing the risks and conditions under which public
instructed his sailors to bind him to the ship’s mast
health considerations can permit xenotransplantation.
and ignore all of his subsequent orders until the island
The contract would fulfill its purpose by allowing the
was safely behind them. Then, he plugged the sailors’
recipient to avoid akrasia, or weakness of the will,56
ears with beeswax so they could not hear and be lured
through a future error in reasoning. For example, the
recipient waives his right to withdraw from the study
by the music. Ulysses, in essence, issued an advance
because he wants the life-saving xenotransplant, but
directive for others to ignore his future orders until a
recognizes the importance of protecting others from a
specified condition was satisfied.
potentially catastrophic epidemic caused by a xenogePsychiatric Ulysses contracts have a similar premise.
neic infectious agent. He is perfectly willing to comply
During a remission, a patient with a relapsing psychiwith life-long surveillance to avoid such an epidemic.
atric illness contracts with the treating psychiatrist for
Ten years later, the possibility of a catastrophic epifuture treatment. The Ulysses contract can “…preaudemic seems increasingly remote, and he finds the
thorize [involuntary] commitment for a patient who
surveillance to be annoying and inconvenient, so he
begins to display symptoms of a relapse, regardless
wishes not to continue in the surveillance program.
of whether the patient consents to commitment at
However, the Ulysses contract he signed before the
that future time.”52 Twenty states recognize psychiatric
advanced directives as valid.53
transplant operation overrides this weakness of will,
A xenotransplantation Ulysses contract could operand the contract keeps him in the program.
ate in a similar manner. It would explicitly state that
The Ulysses contract for xenotransplantation is eththe patient waives the right to withdraw from the cliniically justifiable because there are alternatives to the
xenotransplantation and its accompanying risks. For
cal trial. The contract could outline the surveillance
example, the patient may choose to wait for a human
schedule, as well as the proposed penalties for nonorgan to be donated, accepting the possibility of death
compliance. As long as the xenotransplant recipient is
while waiting, or may choose to reject any replacement
in compliance with the surveillance requirements, the
for his or her failing organ, accepting the inevitabilcontract’s penalties and enforcement would be held
ity of death. In addition, the contract, into which the
in abeyance. If a recipient is deemed noncompliant,
270
journal of law, medicine & ethics
Spillman and Sade
recipient will enter and waive the right to withdraw
from the trial, is explicit and clear.
The Ulysses contract for xenotransplantation also
draws ethical support from the possibility of modification or cancellation in the future. In the psychiatric
Ulysses model, the patient has the right to modify or
cancel the contract only when in remission.57 In the
proposed Ulysses contract for xenotransplantation,
modification or revocation would require the consent of the patient and the clinical trial investigator,
based upon rigorous scientific assessment of infectious disease risks. The risks that seem unknown and
unquantifiable today may be very different in ten or in
50 years. For example, in the 1970s, all recombinant
DNA research was considered to be biohazardous and
required approval by the Recombinant DNA Advisory
Committee (RAC) due to fears about consequences
of tampering with the genetic material. Today, many
high school students perform basic recombinant DNA
experiments in their school laboratories. What a difference time and experience make!
Conclusion
Xenotransplantation creates human chimeras who
pose a risk of novel infectious diseases that are dangerous to society at large. This risk has taken on a sense
of urgency with the emergence of human embryonic
stem cell lines that have been exposed to mouse feeder
cell layers. If those cells are used in human therapeutic
transplantations, then the patients would be subject to
xenotransplantation surveillance protocols.58
The known infection risks of xenotransplantation
can be minimized by careful screening and animal
husbandry; however, the unknown risks of xenogeneic
diseases remain. The potential but unquantified possibility of xenogeneic disease has resulted in a compelling argument for long-term, potentially life-long
surveillance. The U.S. PHS Guideline requires that the
informed consent process include discussion of the
need to comply with long-term or life-long surveillance, which effectively abrogates the subject’s right to
withdraw from a clinical trial. It is ethically disturbing
that the PHS Guideline does not clearly discuss the
need for long-term surveillance in the context of the
subject’s right to withdraw from the study.
Although traditional contract law may not apply
to enforcement of a contract for xenotransplantation surveillance, we believe that a Ulysses contract
might be both ethically justifiable and legally enforceable. As an advance directive to minimize akrasia or
to avoid errors in reasoning, the Ulysses contract for
xenotransplantation would satisfy the ethical imperative of respect for persons and the corollaries of selfdetermination and informed consent. The intended
100 years of transplantation • summer 2007
recipient would be apprised of all the risks, benefits,
obligations, and consequences of accepting the xenograft. Potential recipients would have the options to
accept the contract, to decline the contract and wait
for an allograft, or to accept the consequences of their
end-organ failure. In the future, Ulysses contracts for
xenotransplantation would be modified as new information became available and the risks of infection
clarified.
Acknowledgements
The authors would like to thank Dr. Anne Lyerly of Duke University Medical Center for helpful comments on the manuscript.
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25. Id., at 20.
26. Center for Biologics Evaluation and Research, Food and Drug
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28. Id., at 35.
29. Id., at 36.
30. Id.
31. Id., at 37.
32. Id.
33. See Guidance for Industry, supra note 26, at 49.
34. See Guideline, supra note 1, at 21.
35. Id.
36. See Guidance for Industry, supra note 26, at 56.
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45. D. K. C. Cooper and R. P. Lanza, eds., XENO: The Promise
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46. See Florencio, supra note 43, at 119.
47. United States Supreme Court O’Connor v. Donaldson, 422 U.S.
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48. See Florencio and Ramanathan, supra note 46.
49. Id.
50. Id.
51. Id., at 120.
52. R. Spellecy, “Reviving Ulysses Contracts,” Kennedy Institute of
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53. Id., at 375; personal communication with author, January 10,
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54. Id., at 373.
55. See Sykes et al., supra note 42, at 1103.
56. See Spellecy, supra note 52, at 374.
57. Id., at 375.
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