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January 16, 2003


Winship Bio-Ethicist Develops Research Guidelines for Terminal-Wean and Brain-Dead Patients

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, Ph.D., Research Ethicist for Hematology and Oncology at Emory Universityís Winship Cancer Institute, is lead author on a paper that is presented in the January/February Issue of The Hastings Center Report entitled, Revisiting Ethical Guidelines for Research with Terminal Wean and Brain-Dead Participants. The Hastings Center is one of the countryís leading think tanks on ethical issues.

Dr. Pentz and her colleagues developed these guidelines so that her colleagues could 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 patientís and familyís goals.

In the case discussed in this article, cancer researchers Renata Pasqualini, Ph.D. and Wadih Arap, MD, research biologists in the Department of Genito-Urinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, had shown that if peptides--short sequences of amino acids--are gentically 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 Drs. Pasqualini and Arap had demonstrated the potential in mice, it had not in been demonstrated 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.

Dr. Pentz, a widely published bio-ethicist, worked with Drs. Paqualini and Arap as well as another ethicist at MD Anderson, Anne Flamm, JD, to develop ethical guidelines that involved:
1. Conditions for the proposed research,
2. Eligibility guidelines for appropriate patients, and
3. 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," writes Dr. Pentz 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.

Investigators also included 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 patientís altruistic wishes is important to family members; a research study is an acceptable alternative to organ donation; and the decedentís motives often specifically include the desire to benefit cancer research, the treating physician or the hospital.

Dr. Pentz, Dr. Flamm, Dr. Pasqualini and Dr. Arap 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," writes Dr. Pentz, "that the evaluation begun by this protocol be expanded to consider the impact of such research on families, care providers, and the public."

Dr. Pentz is a widely published investigator and author in bioethics. Her research focuses on ethical issues involved in oncology research, genetic testing, informed consent and privacy. She received her Doctorate of Philosophy in Philosophy from the University of California at Irvine.

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