Research into any promising new drug therapy eventually reaches
a point where the investigation moves from the laboratory to humans.
As medical science reaches new heights, the ethical protocols that
guide research on human subjects must keep pace.
Rebecca Pentz, research ethicist for hematology and oncology at
the Winship Cancer Institute, is lead author on a paper presented
in the January/February issue of The Hastings Center Report
titled, “Revisiting Ethical Guidelines for Research with
Terminal Wean and Brain-Dead Participants.” The Hastings Center
is one of the country’s leading think tanks on ethical issues.
Pentz and her colleagues developed these guidelines so that researchers
may proceed ethically with important translational research while
allowing families of patients to be involved and supportive. For
example, many terminal cancer patients offer to serve as organ donors.
With most cancer patients, however, that cannot happen because of
the extent of cancer within the body. Offering them a research opportunity
might be another way to meet the patient’s and family’s
goals.
In one case, cancer researchers Renata Pasqualini and Wadih Arap,
biologists in genito-urinary medical oncology at the University
of Texas Anderson Cancer Center, had shown that if peptides—short
sequences of amino acids—are genetically attached to a simple
virus known as phage, the phage will bind to the vasculature of
specific organs. In addition, certain peptides will attach to the
vasculature of tumors, which would make it possible to deliver targeted
cancer drugs.
Continued research would lead to possible development of mechanisms
for the targeted delivery of cancer therapies, gene therapies and
imaging agents. While Pasqualini and Arap had demonstrated the potential
in mice, it had not been demonstrated in humans, and the risk to
humans could not accurately be determined from animal studies.
Injection of millions of phage into humans had never been done.
In addition, multiple biopsies would have to be taken shortly after
the phage injection to determine the extent of distribution. Therefore,
the investigators determined that the burden of research would be
unacceptable for anyone with a life expectancy of more than a few
hours.
The potential benefit of the research for cancer patients, however,
compelled the investigators to search for an appropriate population,
and they decided to look to brain-dead individuals, whose circulatory
and ventilatory systems are being maintained mechanically, and “terminal-wean”
patients, whose life support equipment or drugs will imminently
be withdrawn. The primary reason to approach this population was
the experience both doctors had with families in intensive care
units who expressed a dying patient’s wish to donate organs
or contribute in some way to the fight against cancer.
Pentz, a widely published bioethicist, worked with Pasqualini and
Arap as well as their UT colleague, Anne Flamm, to develop ethical
guidelines that involved conditions for the proposed research; eligibility
guidelines for appropriate patients; and guidelines on implementing
the protocol.
“Expanding the pool of potential research participants to
include terminal-wean and brain-dead participants may enhance our
ability to test new agents with minimal harm,” Pentz wrote
in the Hastings article. “Yet we are sensitive to the possibility
that including this vulnerable population may erode respect for
humans as ends in themselves. Our guidelines are intended to prevent
this erosion by limiting both the type of research performed and
the eligibility of participants.”
Among the guidelines is the stipulation that “participants
must have indicated to the health care team or surrogates that they
have end-of-life altruistic goals consistent with such research.”
In addition, in recognition of the stress and grief of family members
after they have authorized a terminal wean, the guidelines stipulate
a one-hour limit on any research procedures.
Pentz and her colleagues conducted follow-up interviews with family
members of participants in the study as well as family members of
terminal-wean patients who were eligible for the study but did not
participate. Three themes emerged from these interviews: honoring
the patient’s altruistic wishes is important to family members;
a research study is an acceptable alternative to organ donation;
and the decedent’s motives often specifically include the
desire to benefit cancer research, the treating physician or the
hospital.
The authors conclude that research on terminal-wean and brain-dead
patients can be performed ethically providing specific guidelines
are followed. They recommend continued discussion of the issue with
a panel of ethicists, researchers and patient representatives.
“We also believe,” Pentz wrote, “that the evaluation
begun by this protocol be expanded to consider the impact of such
research on families, care providers and the public.”
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