Should dying patients be research subjects?

Ethicists worry research would erode respect

An experimental blood oxygenation device has the potential to help thousands of patients with severe emphysema or other lung conditions. The device has been thoroughly tested in laboratory animals, but human trials would involve major invasive procedures for research participants and place them at very high risk of death or serious complications.

Instead, researchers have tested the device in brain-dead patients just prior to the withdrawal of mechanical ventilation. Researchers gathered information about how well the device improved oxygen levels in the subjects’ blood, without conducting painful experiments in living patients expected to recover and continue their lives.

At a noted cancer hospital, researchers needed to test an innovative therapeutic drug designed to attack tumor growth while leaving healthy tissue undamaged. Instead of injecting the product into research volunteers — which would have necessitated multiple tissue biopsies to ascertain whether intended tissue targets were affected — researchers first tested it on "terminal wean" patients, those patients who were being removed from mechanical ventilation and respiration and who were expected to die within the next few hours.

These are just a few examples of research being conducted nationwide using dead and nearly dead patients as subjects. Such investigations allow researchers and clinicians to study new and risky procedures and treatments in a realistic way, without putting patients at risk of harm.

However, some ethicists worry that more oversight is needed to ensure research of this type doesn’t erode respect for human beings, both living and dead.

Viewing deceased or dying patients as possible subjects of research from which they cannot possibly benefit increases the risk that patients at or near the end of life will be seen as a means to an end, rather than retaining the dignity they should have as individuals, notes Jacqueline Glover, PhD, associate professor in the Center for Bioethics and Humanities and the department of pediatrics at the University of Colorado Health Sciences Center in Denver.

Glover and other experts in bioethics and medical research participated in a seminar on developing ethical guidelines for research including patients at the end of life, held Feb. 24 at Emory University in Atlanta.

Institutions and researchers considering such protocols need guidance on the unique ethical ramifications of these projects, Glover adds. "We have to be concerned with protecting vulnerable populations, but also with promoting public health and needed research. What are the societal implications, what are the conflicting interests, and what is the role of bioethics in fostering dialogue in the community?"

A wide variety of research using deceased and dying subjects has been proposed in several medical specialties, says John Kavanagh, MD, professor at the University of Texas M.D. Anderson Cancer Center in Houston.

Especially in highly technological fields such as interventional radiology or laparoscopic surgery, where new techniques, procedures, and instruments emerge frequently and clinicians are pressed to develop proficiency quickly, practicing on deceased patients first can prevent serious errors later.

Animals often are not appropriate substitutes because they do not have the same anatomy, Kavanagh notes. Currently, clinicians often use flash-frozen human cadavers, but these models also do not provide a realistic simulation of what performing an actual procedure is like or how living human tissues and systems will react to a procedure or treatment.

Research into the pharmacodynamics of new medications also could be improved by using brain-dead patients or terminal-wean patients prior to the withdrawal of life support, he says.

One of the first things clinical investigators need to know about a new drug is how it acts once it is inside the human body. Researchers must give the drug, then collect numerous biopsies and blood samples to determine where the medication went and whether it acted as researchers believed it would, he says.

Studies benefit future patients, not subjects

"These studies rarely, if ever, benefit the patient; the information is needed for future patients," Kavanagh says. "Usually, these are part of Phase I trials, which are dose-determining trials. Participants in these trials usually receive less-than-optimal doses of the drug, and participation in the trial frequently requires subjects to travel and stay in a hotel near the hospital. Morbidity from participation is not usually very bad. But the majority of Phase I trials fail and never progress to Phase II."

The administration of an experimental drug into a nearly dead patient with intact major organ systems could yield the same information.

A number of institutions and ethics committees have examined the ethical issues these protocols present and are developing guidelines for determining which projects to allow, which to prohibit, and what subject protections need to be in place, says Rebecca D. Pentz, PhD, associate professor and research ethicist for hematology and oncology at the Winship Cancer Institute at Emory.

If institutions want to allow research protocols involving dead or dying patients, there are a number of issues to consider:

1. How important is the research? Several authors have stipulated that the proposed investigation must address an important clinical problem, usually one that would be difficult to study in any other population, Pentz says.

2. Which patients are eligible? Some institutions permit research involving brain-dead patients but not patients defined as nearly dead — those who physicians believe to be within a few hours of death. And some institutions feel that these populations should be used only as a last resort. Opinions also differ about whether organ donors and autopsy candidates should be included in or excluded from consideration.

3. Should informed consent be obtained? Almost all ethicists agree that investigators should obtain informed consent from family members, and some have added that subjects should have previously indicated to family or to caregivers some willingness to participate in research or to have their body or tissues used for research purposes after their deaths.

4. What are the time limits? A particularly thorny issue is the duration of the proposed research intervention, Pentz notes. Almost all of the published guidance indicates that the intervention should be of short duration and that deceased patients not be maintained on life support for long periods of time solely for the purpose of conducting a research protocol, she explains.

5. What if the patient dies during the protocol? For research involving terminal-wean patients and patients who are near death, the possibility exists that death will occur during the intervention, Pentz notes. Ethics committees must decide what investigators and clinicians will do if this happens. For example, must investigators halt the intervention? Will family members be allowed to be present during the protocol?

One of the most difficult quandaries faced by medical ethicists involves the need to separate decisions about inclusion in research from the decision to terminate life-support measures, notes Glover.

Some institutions require that a death certificate be issued prior to inclusion of the patient in a research protocol, and some also require that the decision to place the patient on a terminal wean be made by a clinician independent of the research protocol.

The impact of participation in the research protocol on the deceased person’s family also must be considered.

Family members are not always in agreement about whether their loved one would have wanted to be included, and they are not always of one mind in terms of knowing what to expect, Glover adds.

Research protocols involving the nearly dead present unique ethical dilemmas, she adds. Where is the distinction between a living person and one who is "nearly dead" — and, she asks, should there even be a distinction?

Although clinicians may feel in particular situations that they can predict with some certainty that a person will not live longer than a few more hours, it’s difficult to argue that these patients should somehow be considered "less than alive," she says.

Research on dead patients falls into gray area

Research involving deceased patients actually falls into a gray area in terms of federally mandated human subject protections, says Michael A. DeVita, MD, FACP, assistant professor of anesthesiology and critical care medicine at the University of Pittsburgh Medical College and chair of the college’s ethics committee.

According to federal regulations, institutional review boards are only authorized to monitor research involving living human subjects. Many are understandably reluctant to evaluate protocols involving the dead because of fears that a federal audit of their records would reveal different criteria used to judge protocols involving dead participants and those involving living subjects.

Medical center ethics committees usually only consider issues related to the clinical treatment of patients at their facility, and typically have no jurisdiction over organs, tissues, or other materials that may come into a facility from somewhere else but involve investigators at that center.

After receiving a request from a clinician to study an artificial blood oxygenation device in brain-dead patients, the University of Pittsburgh College of Medicine decided to form a separate committee, the Committee on Research Involving the Dead (CORID), to evaluate such protocols.

University officials said such protocols did present some difficult human subjects concerns that were separate and distinct from the concerns posed by research involving living subjects.

Officials noted that researchers aren’t able to definitively quantify all the potential risks to subjects; that abuses of potential subjects could occur; and that they would not easily be discovered if they did occur, DeVita says. For these reasons, CORID was formed. The goals of CORID are:

  • to protect deceased patients;
  • to protect family members of deceased and dying patients;
  • to provide guidance to investigators;
  • to provide ethical standards for how similar research should be monitored.

Among the issues that CORID has had to consider is when to seek consent for a research protocol from family members of organ donors, because the Uniform Anatomical Gift Act permits research on donated organs and tissues if the person has consented to organ donation.

However, the committee determined that investigators must seek additional consent from family members if the study involves an unusual procedure or degree of bodily invasion.

In determining the need for family consent, CORID considers the degree of invasion the protocol would involve, the potential benefit to be obtained by the information found in the study, and whether the potential benefit outweighs the degree of invasion involved.

The committee also has developed guidance regarding research processes and procedures, such as how tissue samples will be collected and stored, whether family visitation can occur during the study procedure, and whether participants in the study still may be able to have an open-casket funeral.

CORID also established time limits on how long study interventions could take, where brain-dead patients could be maintained during the study intervention, and which health care personnel would be involved in providing clinical care.