Research on the dead: Standards are required
University committee examines protocols
A cardiovascular surgeon develops an experimental intravascular blood oxygenation device that has the potential to eliminate the need for mechanical ventilation in severely injured patients.
However, testing the device in human patients would be unethical because of the great risk of harm, and the still-unknown chance for benefit.
The surgeon wants the opportunity to test the device in patients who have been declared brain-dead prior to the withdrawal of life support. With no remaining brain function, these patients are no longer living, and so face no risk of harm. But they have intact, functioning cardiac and circulatory systems, which would allow clinical researchers to gather the vital information.
If you think this sounds logical yet gruesome at the same time, you’re not alone.
This scenario actually occurred in 2001 at the University of Pittsburgh.
Surprisingly, the proposed research protocol fell outside the purview of the university’s institutional review board because the intended subjects were no longer living. Federal regulations stipulating human subjects protections do not apply.
"The IRB saw no need for approval, but the investigator still wanted some oversight and opinions on the appropriate way to proceed, and came to the ethics committee for consultation," says Michael A. DeVita, MD, FACP, assistant professor of anesthesiology and critical care medicine at the University of Pittsburgh Medical College and its ethics committee chair. "This was our test case."
After much study by the ethics committee, and discussion with the administration, the university decided to establish a separate panel, the Committee for Oversight of Research Involving the Dead (CORID), to evaluate and approve protocols using deceased subjects.
An emerging research arena
As medical technology improves and treatments become more complex — and involve more risk — clinicians are increasingly looking to study particularly difficult interventions in brain-dead patients. Lifesaving therapies could be perfected without endangering patients who need help now, and such protocols could prevent medical errors in future patients.
Using the dead for research purposes is actually not new.
For many years, medical residents have practiced difficult procedures, such as endotracheal intubation or central line insertion, on recently deceased patients.
Investigators have often collected tissue samples, such as liver biopsies, from brain-dead patients in order to study the effects of a particular condition.
And some investigators have conducted other research on the bodies of brain-dead cadavers. Because the practice is not regulated and not often discussed, little information is available, DeVita says.
However, as such studies grow in number and variety, and involve different levels of complexity, researchers are beginning to question whether more oversight is needed.
For example, many inherently feel that the families of brain-dead patients should give consent for such protocols — particularly if they are invasive or require a significant amount of time. But when should consent be required? Who should obtain consent and what information should be provided to family members?
Maintaining brain-dead cadavers on life support also raises other ethical concerns. For example, should dead patients be kept breathing, their blood circulating, so that we can perform research? And how long should a dead person be left on a ventilator so that his or her body can be used?
However, federal regulations only require the oversight of an institutional review board if a study involves living patients, DeVita explains. Most people feel that some oversight is necessary, however.
The question is, where to draw the line between the stringent protections required to protect living people, and the attitude that "if the patient is dead, do whatever you want," he says.
In deciding how to proceed, Pittsburgh officials first looked to the institutional review board to determine whether they could appropriately review these protocols, even though federal law does not require it.
There are several reasons that was not workable.
Like most IRBs, the one at Pittsburgh was already overloaded with protocols involving human subjects. And members were concerned that if they used different criteria for evaluating research on the dead, an audit by officials from the U.S. Office of Human Research Protections would land them in hot water.
"There is no established avenue for allowing IRBs to use different standards for different types of research," DeVita says. "There was concern that they would be cited and it would endanger other research."
In deciding whether a formal oversight process was needed, university officials and the ethics committee considered three things: 1) Are researchers in this area able to quantify the potential risks to subjects well? 2) Did the potential for abuse exist? 3) And if abuses occur, would they be easily discovered?
The answer to all three questions, they felt, was yes.
Originally, they felt the protocols could be reviewed by the medical school ethics committee, but concluded that this would not be sufficient. The ethics committee only had jurisdiction over studies involving patients at that institution, but would not have influence over investigators at other sites or deceased patients or tissue materials brought in from other places. A separate panel was needed.
The goals of CORID, they decided, would be to provide guidance to investigators, and protect the deceased people and their families.
Though potential subjects would be deceased, clinicians still have an ethical responsibility to honor — as best as possible — the person’s preferences and values about whether or not they would want their body to be used in a research protocol. And there are general issues to consider about respect for human corpses.
"Some things are reasonable to do, and some things are just not reasonable to do," he says.
There also are confidentiality issues to consider, DeVita continues. Researchers could discover new information about the person.
Families may also have concerns — they have dispositional rights to their family member’s body that should not be interfered with. So clinicians and investigators need to be sensitive to their feelings with regard to appropriate treatment of the cadaver.
As for investigators, most admit that they don’t know the limits — what is reasonable research conduct? And they want to operate with a set of rules, DeVita says.
CORID’s first goal was to develop a set of ethical standards of practice for investigators to follow.
"We started out with the ethical principles and then developed standards based on those principles," DeVita says.
To conduct research involving dead patients, investigators must demonstrate that:
- their study has scientific merit;
- they will be able to provide informed consent to family members;
- the protocol would involve an unusual or unexpected use of a cadaver, but that the intervention would be for only a limited time and conducted in an appropriate location;
- investigators have a plan to provide feedback on the research to the family members;
- the subjects’ confidentiality will be protected;
- investigators will disclose conflicts of interest;
- investigators will document that their study will not interfere with possibility of organ donation;
- documentation will be made of the expect impact on hospital resources and the financial impact of the subject’s family.
Since CORID’s formation, it has received 29 submissions of protocols for review from 17 different departments, says Mark Wicclair, PhD, professor of philosophy and adjunct professor of community medicine at the University of Pittsburgh Center for Bioethics and Health Law.
"CORID review is not limited to brain-dead cadavers, it can review any study involving deceased patients and use of cadavers," he notes.
Of the submissions received to date, 20 have involved proposed use of cadavers and tissues obtained at autopsy, five have been case studies, three have involved use of brain-dead patients, and one involved use a cadaver without a functioning cardiovascular system in a clinical setting.
The majority of investigators were referred to CORID from the institutional review board, and involved investigators who were unaware of the separate committee, Wicclair says.
Twenty-six of the submissions were approved and three received conditional approval — the committee asked for protocol modifications or more review from investigators.
"We did not reject any outright on ethical grounds," Wicclair notes.
CORID now is focusing on other issues involving appropriate research processes and procedures, including how tissues should be collected and stored, whether family visitation during the study intervention should be permitted and what policies and procedures need to be in place; and what policies should be about the physical effects the study intervention might have on the body.
There has been confusion on the part of some investigators about providing appropriate informed consent to family members and maintaining confidentiality of the deceased person involved, Wicclair says.
And in studies involving brain-dead patients, questions about who should approach the family to seek informed consent for research have come up.
"Who should be responsible for getting informed consent?" Wicclair asks. "Is it the organ procurement organization representative or is it going to be the investigator talking to the family?"
CORID members felt that it ought to be the investigator so that the research protocol would not be confused with consent for organ donation.
The duration of the research protocol has also been a concern and the committee agreed that a set limit had to be in place.
"There are concerns about resource utilization, the impact on the family and the question about respect for the cadaver," he says. "We were agreed that it could not go on indefinitely, but we had to establish what was long enough and what was too long."
After considerable debate, the committee agreed on a time limit of 72 hours — interventions of a longer duration would not be allowed.
In examining the university’s experience with CORID, it has become clear that research involving the dead was neither rare nor limited to only a few departments, Wicclair says.
Investigators have been able to satisfy ethical standards of research established by the committee, and the committee has served not to thwart the research protocols but to facilitate such research and promote appropriate ethical standards, he states.
Guidance on research involving the dead
- Coller BS, Scudder LE, Berger HJ, et al. Inhibition of human platelet function in vivo with monoclonal antibody: With observations on the newly dead as experimental subjects. Ann Intern Med 1988; 109:635-638.
- Coller BS. The newly dead as research subjects. Clin Res 1989; 37:487-494.
- LaPuma J. Discovery and disquiet: Research on the brain dead. Ann Intern Med 1988; 109:606-608.
- Pentz RD, Flamm AL, Pasqualini R, et al. Ethics framework for research in terminal wean patients and brain-dead subjects. Hastings Center Rep 2003; 33:1-8.
- Committee for the Oversight of Research Involving the Dead (CORID). Policy for research involving the dead. Crit Care Med 2003; 31:S391-S393.
- Robertson J. Research on the brain dead. IRB 1980; 2:4-7.