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Xenotransplants
Moving Ahead Too
Quickly for Some
This is the second of two articles on
xenotransplantation.
Despite fears that retroviruses embedded in swine DNA may confer a risk
of cancer and other diseases on the
recipients and their close contacts, the
Food and Drug Administration has
decided to permit some clinical trials of
pig-to-human transplants to resume and
a limited number of others to begin.
However, the regulatory agency is proceeding cautiously and will not be going
it alone in its oversight of the trials.
Instead, it will collaborate in this
endeavor with its sister U.S. Public
Health Service agencies- the National
Institutes of Health and the Centers for
Disease Control and Prevention. Indeed,
that will be true whether pigs or other
species are the donor animals.
Outlines of the plan were featured at
a meeting on xenotransplantation- i.e.,
cross-species transplants of cells, tissues, or entire organs - recently convened at NIH by the PHS.
At the heart of the PHS precautionary strategy is a set of guidelines led by
the requirement that donor animals be
born and raised in "specific pathogenfree" (SPF) environments that are
mostly, but not entirely, germ free. Although most companies aspiring to a
niche in the xenotransplant market already comply with this requirement,
there have been some exceptions.
An example is a company that sponsored a clinical trial of a bioengineered
painkiller. In this trial, cells present in
the adrenal glands of cattle that naturally secrete analgesic compounds were
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placed in a device that was floated in the
cerebrospinal fluid of terminal cancer
patients to relieve their pain. While the
calves that supplied the cells had been
quarantined and screened for infectious
agents before slaughter, they were
bought from farms that did not have SPF
facilities. In the future, clinical trials for
either cancer or noncancer chronic pain
will meet FDA's guidelines only if cells
from SPF animals are used.
Safeguards
Also in the plan are a tissue bank that
will house samples from both donor
animals and
recipients and
a computerized on-line
registry (for
authorized
users only)
that will track
the health of
every donor
animal and the
herd from
Dr. Fritz Bach
which it
comes, as well as which trial patients get
which animal's body parts.
Philip Noguchi, M.D., director of
FDA's Division of Cellular and Gene
Therapy, told the meeting that a pilot
study of the registry will soon begin so
that any necessary changes can be made
while the number of clinical trials is still
small. Amy Patterson, M.D., his deputy
and an expert on cross-species trans-
plants, provided further detail in a later
interview.
"Suppose," she said, "that you're a
trial patient who has a pig xenograft and
that, before you got the graft, that pig
had been quarantined for 30 days and
passed all the tests that qualified it for
clinical use. But also suppose that it's
the day after your surgery and that pig
came from a herd where there is now an
outbreak of viral illness that has a 40day incubation period. In that case, the
pig that was your donor might easily
have been infected, too.
"Ordinarily," she continued, ''your
doctors would have no way of knowing
this because the infection couldn't have
been detected when the animal was
slaughtered. Nor would they be able to
trace your donor pig to a particular herd.
The registry will quickly provide both
sorts of key information and so should
be a powerful surveillance and monitoring tool."
New Panel?
Patterson added that the registry also
can be expected to make it easier to
learn whether any unexpected infections
that xenograft recipients develop come
from the donor animals. This is an important point, Patterson noted, "because
the drugs given to transplant patents to
control graft rejection increase their
susceptibility to infection anyway.
"Moreover, if- and it's a big ifxenografts do cause some infections in
people, we don't yet know whether only
the patients will be at risk or also their
close contacts and, by extension, the
community at large. PHS and its agencies think the registry will be invaluable
in addressing these public health concerns."
Meanwhile, the Department of
Health and Human Services (the parent
Journal of the National Cancer Institute, Vol. 90, No. 5, March 4, 1998
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agency for the entire PHS) hopes to
create a new panel that would do for
xenotransplantation what NIH's Recombinant DNA Advisory Committee does
for gene therapy: it would review proposed clinical trials in public and encourage broad public participation in its
deliberations but have no regulatory
authority.
However, plans for the arrangement
are provisional because the number of
advisory committees the Executive
Branch of the federal government can
have is limited by law, and that lirri1t. has
been reached.
The uncertain future of the proposed ·
advisory panel aside, not everyone at
the recent meeting was persuaded that it
is prudent to allow clinical trials to take
place while knowledge about the potential risks of cross-species transplants is
so fragmentary that they might endanger
public health.
The most vocal of the doubters was
Fritz Bach, M.D., of Harvard University
in Boston. He and Harvey Fineberg,
M.D., Ph.D., the University's Provost,
are the leaders of a group of nine scientists that in the Jan. 22 issue of Nature
and the February issue of Nature Medicine called for a broad public debate on
the matter and a moratorium on the trials
in the meantime.
"Yes, the meeting at NIH was an
open meeting," Bach said in a later
interview. "But many who were there
had a financial or career interest in
making xenotransplantation pay off:
either that or they were patient advo-
Cross-species Transplants May Pose Risk to Livestock
Stewart Jessamine, M.B., Ch.B., D.P.H., came halfway
around the world to represent his country at January's conference on xenotransplantation at the National Institutes of
Health.
An official at New Zealand's Ministry of Health, in Wellington, Jessamine was an invited speaker at the meeting because in
1996 a handful of diabetic New Zealanders were experimentally treated with porcine pancreatic islet cells before there was
published information that would
have alerted him and his colleagues
to the controversial aspects of crossspecies therapies.
Since then, some guidelines have
been published and Jessamine reported that he is now able to turn to
agencies like the U.S. Food and
Drug Administration for technical
expertise that is lacking in his nation
of 3.5 million people.
Dr. Stewart Jessamine
New Zealand's health ministry
has been asked to approve another
clinical study involving viable animal tissue and it needs outside help to evaluate the request. However, Jessamine was at
pains to add that "when developing public policy in
xenotransplantation, we consider not only the scientific evidence, but also the cultural safety of the procedure."
In New Zealand, he said, cultural safety includes the participation of the 15% to 20% of the population that is Maori in
health policy decisions. But it also includes anticipating
Journal of the National Cancer Institute, Vol. 90, No.5, March 4, 1998
possible problems for a country whose economy heavily
depends on the export of meat, hides, wool, and other animal products.
In that regard, Jessamine said that he had been struck by the
"very little research" that has been done on whether the ability
of viruses carried by xenografts to jump species barriers, and
so infect people, may also work in reverse. In that case, the
alien viruses might- through mutations or other unanticipated changes - spread from a transplant recipient not into
the human population (though, perhaps there, too) but back
into livestock.
"I am not saying that this scenario could or would come to
pass," Jessamine said in an interview. "But neither," he said,
"is it wholly implausible: the more so, because most of our
citizens who would be candidates for cross-species trials either
live on ranches and farms or have close ties to them."
Although Jessamine was the conference's only speaker
from a small country, there was a clear recognition by many at
the meeting that New Zealand's concerns are not unique and
that cross-species transplants merit attention from governments throughout the world.
It is for that reason that the agencies of the U.S. Public
Health Service are consulting with their counterparts in
France, Canada, England, and at the World Health Organization, which is based in Geneva, Switzerland. And it is also for
that reason that, just as xenotransplantation policy will continue to evolve in the United States, so will it do so elsewhere.
-Judith Randal
NEWS
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