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What's End of Life Got to Do With It? Research Ethics With Populations at Life's End

^a Einstein Center for Urban Health Policy and Research, Thomas Jefferson University/Jefferson Health System, Philadelphia, PA

Correspondence: Etienne J. Phipps, PhD, Albert Einstein Healthcare Network, Center for Urban Health Policy and Research, One Penn Boulevard, Wister 4442, Philadelphia, PA 19144. E-mail: phippst{at}einstein.edu.

	Abstract

TOP Abstract Ethical Guidelines Doctrine of Informed Consent Vulnerable Patient Populations Investigators How Different Is End-of-Life... Are the Issues Sufficiently... Summary Directions for the Future References

 
Purpose: This study addressed key concerns that gave rise to the question of whether special guidelines were needed to monitor research at the end of life. Design and Methods: Summary of established ethical and legal guidelines that govern the conduct of research with human subjects, with discussion of issues relevant to populations at life's end. Discussion of whether special guidelines are indicated focuses on four questions concerning: (a) time periods; (b) methods and approaches; (c) informed consent; and (d) obligations of researchers. Results: Although research involving patients at end of life does present important ethical and moral challenges to researchers and should be scrutinized carefully by institutional review boards (IRBs), special guidelines are not required. Implications: Closer examination of the dimensions discussed will enhance the research endeavor and model the qualities for which end-of-life research should become known.

Key Words: Institutional review boards • Ethical guidelines • Vulnerable patients

A 70-year-old man is injured as the driver of a motor vehicle that collides with a tow truck. CT and radiologic studies reveal severe brain injury, requiring partial lobectomies. At the time of admission to acute rehabilitation 2 months postinjury, the patient appears to be vegetative. On the brain injury unit, his adult children maintain a constant vigil, praying for his recovery.

An 80-year-old woman with moderate dementia suffers a cardiac arrest at home. Her daughter calls 911, and paramedics arrive within 9 minutes. She is given CPR, intubated, and taken to the local emergency room. The emergency room team believes, on the basis of "down time" and the results of an EKG showing anoxic encephalopathy, that she is unlikely to recover. The team plans to remove her from life support once they get consent from the daughter.

A 63-year-old male with advanced lung cancer is being treated in the hospital's cancer center. He lives alone and always comes to his chemotherapy sessions by himself. He seems distant and aloof, never wanting to talk about his health with the nurse who is most involved in his care. He has a respectful relationship with his oncologist, whose advice he seems to follow without question.

A 75-year-old woman with advanced chronic obstructive pulmonary disease and Parkinson's disease is enrolled in hospice. She moved into her daughter's home after her last hospitalization. She has lost considerable weight and is unable to ambulate without assistance. She is able to converse with moderate coherence at different times during the day. She is not expected to live another month.

These are the types of people who are the subjects of investigations around the end of life. They all tug at our heartstrings and, at the same time, offer opportunities to better understand phenomena, test treatments, and improve care through our research efforts. Investigations might range from studies of a new investigational device to restart the heart with the soon-to-be-deceased woman in the emergency room, to clinical trials offered to the advanced cancer patient, and to descriptive and ethnographic studies of how the family of the woman on hospice care deals with her dying. These studies, and the lives they involve, require us to examine closely whether there should be special, more stringent guidelines governing research with these populations.

This article addresses key concerns that give rise to the question of whether special guidelines are needed for research at the end of life. Although the established ethical and legal guidelines that govern the conduct of research with human subjects provide the general framework for discussion, the experiences of individuals dealing with end of life are the focus. These issues are discussed as they pertain to end-of-life research. Whereas the end of life does present important ethical and moral challenges to researchers and should be scrutinized carefully by institutional review boards (IRBs), special guidelines are not required to promote and ensure the ethical conduct of research at life's end.

	Ethical Guidelines

TOP Abstract Ethical Guidelines Doctrine of Informed Consent Vulnerable Patient Populations Investigators How Different Is End-of-Life... Are the Issues Sufficiently... Summary Directions for the Future References

 
Ethical guidelines in research with human subjects are aimed at protecting patients from harm and coercion and at ensuring informed participation. The historic commissions and proceedings—including the 1949 Nuremberg Code 1946, the 1964 Declaration of Helsinki (World Medical Association 1989), The President's Commission (President Commission for the Study of Ethical Problems in Medicine and Biobehavioral Research 1981), and the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979)—codified parameters, approaches, and obligations of researchers.

There are basic ethical principles that apply to a consideration of research ethics: autonomy or respect for persons; beneficence and nonmaleficence, to maximize possible benefit and minimize possible harms and to do no harm; and justice, to formulate a fair distribution of benefits and burdens across the identified population. This article will not address all the principles related to research ethics, but rather will focus on the application of these key principles to research at the end of life.

	Doctrine of Informed Consent

TOP Abstract Ethical Guidelines Doctrine of Informed Consent Vulnerable Patient Populations Investigators How Different Is End-of-Life... Are the Issues Sufficiently... Summary Directions for the Future References

 
Informed consent is the educational contract we use to enroll participants in research. Its purpose is to explain the study's purpose and methods, risks, benefits, alternatives to study treatments, and the rights of research participants (Appelbaum, Roth, Lidz, Benson, and Winslade 1987; Sloan and Resnick 1993). Although the content of informed consent is well described, the process is less so. It is well known that the presentation and the interaction among participants can shape interpretations of the research at hand. For example, how a study is presented to potential participants can result in what Appelbaum and colleagues 1987 refer to as therapeutic misperception in which research participants believe that there is a direct benefit to be obtained from participating in research, when in fact there may be none. The process of informed consent involves overt and subtle messages about the benefits to be gained from participation that can include elements of persuasion, power differentials, and, at times, undue influence.

	Vulnerable Patient Populations

TOP Abstract Ethical Guidelines Doctrine of Informed Consent Vulnerable Patient Populations Investigators How Different Is End-of-Life... Are the Issues Sufficiently... Summary Directions for the Future References

 
Informed consent also involves the important component of voluntariness (Beauchamp and Childress 1989). Participants should decide of their own free will that, after being informed about a study, they agree to participate. Participants are also to understand clearly the potential ramifications, should they choose to refuse participation. Requiring potential participants to be capable of understanding the risks and benefits of participation and the study itself is a critical safeguard to ensuring that participation is not coerced.

Although all potential study participants have rights to be protected, vulnerable patient populations are identified as groups or individuals who cannot give consent that is truly informed or truly voluntary. These include mentally retarded persons, children, and prisoners, who may be more likely to feel or be coerced by others into participating in research. Vulnerability has been extended by some to include students, subordinates, and patients, who might consent to being part of a study as a result of being pressured from someone in a higher position of authority (Dunn and Chadwick 1999).

Many factors or circumstances, in addition to being a member of a group identified previously, can render patients vulnerable. Patients are vulnerable by virtue of their health status, their placement in an institutional setting, their language and communication skills, or their cognitive abilities. In some circumstances, such as those described previously, the status of vulnerability excludes individuals from participation in research. In other circumstances, surrogates, either formally or informally appointed, may be used to provide consent. However, the bases for how the parents of the severely brain-injured 18-year-old decide to enroll him in a study are not clearly specified. Should they be dependent on any previous statements about research? Should they be based on knowing whether he would want to be enrolled in a study that would ensure his continued living, albeit at an exceedingly low level of cognitive functioning? Or should the decision be based on what the parents want, because he is a minor? Should the model and standards used in medical decision making with patients at the end of life apply to research as well? These are questions about decision making for others and research enrollment that seem particularly important at the end of life.

	Investigators

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Investigators, in general, are motivated to increase knowledge, improve treatment, and generally contribute to scientific progress. Clinician investigators who are also involved in the care of patients they want to study often have dual loyalties and conflicts of interest when it comes to research. In their roles as physicians or nurses, their loyalty is to the patient. In their role as researcher, their loyalty is to the research effort. It is difficult to fulfill both roles well with equal loyalty.

Good research requires interesting questions and solid methodologies. In some research involving randomization and different treatment arms, sometimes including the use of placebos, we require belief on the part of the investigator that clinical equipoise exists. This means that, on the basis of available data, competent physicians would be willing to have their patient in any arm of a randomized trial, because no arm has been established as clearly preferable (Passamani 1991). With placebo-controlled trials, there should be the additional assurance that randomized individuals will not be at excess risk and will not receive substandard care, compared with others in the study. With qualitative research, which usually does not involve randomization, the concept of equipoise could also apply—the need for qualitative researchers to believe that their research questions are valid and have not been answered and to be willing to have their patients participate in a process that they believe will not cause them harm.

	How Different Is End-of-Life Research?

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End-of-life research as a topic area is often associated with some recognition and acceptance of life's end and may be distinguished in this way from clinical trials with patients with advanced disease, also at the end of life, but where the endpoints may be reduction of tumor size, remission, or extended life. For example, it would be surprising to hear oncologists refer to their clinical trials with advanced disease as "end-of-life research," though many studies certainly address this phase. Research and study questions around the end of life frequently seek to investigate the who, what, why, where, when, and how of dying, as well as approaches to improving quality of remaining life, although one could legitimately consider end-of-life research to include studies aimed at prolonging life and increasing longevity.

Although much of end-of-life research is associated with terminal illnesses, there are many different end-of-life trajectories (Field and Cassel 1998; Glaser and Strauss 1965; McCormick and Conley 1995; Pattison 1977). The deteriorating disease processes, rapid or slow, recurrent or predictable, visible or invisible; the unexpected motor vehicle event that ends life or results in severe brain damage or worse; the ongoing decline into Alzheimer's—all present different medical, social, and behavioral trajectories that are potential topics for end-of-life research. Practically speaking, it is difficult to put a frame around end-of-life research, although there may be some commonality among the views of researchers interested in this topic. These might include interests in quality of life, subjective views of patients and caregivers, and optimal modes of care at the end of life, to name a few examples.

	Are the Issues Sufficiently Distinct From Other Research?

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The argument that special guidelines are not indicated focuses on responding to four specific and interrelated questions.

1. Are the time periods and the potential research participants living in those periods significantly different from other time periods and other participants?
   
2. Do the methods and approaches of recruitment and enrollment present significantly different risks or burdens to potential participants?
   
3. Are there significantly increased concerns about the content and process of informed consent?
   
4. Are there additional obligations and responsibilities that are significantly different for researchers and their teams working with these populations?
   

Question 1: Are the Time Periods and the Potential Research Participants Living in Those Periods Significantly Different From Other Time Periods and Other Participants?
Often from the most difficult and painful topics we can learn the most about the human experience. The end of life is one of those topics and should be assumed to be associated with heightened medical, physical, emotional, and often spiritual vulnerabilities of potential research participants and of those in their lives. Those individuals who are part of the patient's world—be they friends, family, or spiritual counselor—often play an important role in patient decisions to enroll in research protocols, in compliance, and in continued participation in the research effort. Participants dealing with the end of life are usually facing challenging, sad, and often heartbreaking times.

In research on end of life by myself and several colleagues (Phipps et al. 2002), we found that patients who refused study participation reported feeling too physically and emotionally overwhelmed by their illness and were more likely to report additional caregiving responsibilities (compared with participants) that left them little time, energy, or interest to be a part of a study. Caregivers who refused were likewise overwhelmed with caring for the patient and their own emotional and physical health.

Although proximity to death strikes us as an inherently vulnerable time, how do we compare it with the experiences of other patient populations who are facing medical traumas, such as a devastating diagnosis, amputation, organ transplant, or severe brain injury? Indeed, the vulnerabilities of many at the end of life are profound and are a substantive reason to be concerned about research with these populations. However, recognizing the impact of health crises and medical events on the lives of potential research subjects is something that needs to be applied across all research with human subjects, not just with those in the various trajectories associated with the end of life.

Question 2: Do the Methods and Approaches of Recruitment Present Significantly Different Risks or Burdens to Potential Participants?
The vulnerability of populations dealing with the end of life heightens the need to engage in research that will, on balance, provide more benefit than burden and limit potential harms. Recruitment of patients at the end of life into research studies may increase harms, for example, if their privacy is transgressed by identifying them when they do not want to be identified; if emotional upset is experienced as a result of what is said to them about the study or how it is said; if false hopes are presented in an effort to recruit them; if their death is precipitated as a result of being in a study; or if their dying is made more painful than would have occurred otherwise. On the other hand, there may be unanticipated benefits of study participation. For some, benefits may be so simple as feeling useful or having someone listen to them. Participants may also be able to discuss concerns that are important to them in the context of the study and derive psychological benefit from participation that helps them to cope.

Standard recruitment practices—as they happen in real life, not how they are reported—are known to bypass ethical and legal standards regarding patient confidentiality and privacy. The drive to recruit patients to meet targeted sample sizes fuels the fire to find patients in the most expedient ways (Phipps, Fleetwood and Piraino 1999). Identifying eligible patients is often done by going onto a hospital floor and talking with nurses or residents or by accessing medical records. The existing practices to identify and recruit patients into research will undoubtedly come under additional scrutiny with the Health Information Portability and Accountability Act as access to patient data for recruitment purposes, by someone other than the immediate medical team, will become increasingly more difficult to do.

There is a need, however, to ensure that recruitment methods at the end of life are consistent with existing legal guidelines and institutional requirements. This is where IRBs have an important role. Although we know that there are many limitations on the time and ability of IRBs to provide detailed review and oversight, they still remain the most identifiable review body. With research at the end of life, IRB review should address the recruitment methods with additional, though not different, scrutiny when patient participants are either terminally ill and/or decisionally incapable.

Question 3: Are There Significantly Increased Concerns About the Content and Process of Informed Consent?
The informed consent process is one of the more problematic aspects of research around the end of life. Regardless of the patient's vulnerability and the way potential participants are identified, it is the consent process and resulting document that are used to prove that participation in the research is voluntary and not coerced. We know that in medical treatment, decisionally capable patients make decisions about their treatment, and in their absence, we turn to surrogates. The rights, opportunities, and abilities of decisionally capable patients to enroll in end-of-life research at his or her own discretion are no different from other persons and other studies. We have found that many of these individuals welcome opportunities to discuss topics that their physicians and families avoid. They benefit from being able to engage in conversation and are often willing to share their experiences with a stranger. Many of these individuals do not enroll in end-of-life research without discussion, encouragement, or shared decision making with their families.

A significant proportion of end-of-life research, however, is designed to involve individuals who are unable to make decisions about research participation or about anything for that matter. We need to give more attention to the topic of how surrogates make decisions to enroll decisionally incapable persons in research in general (Phipps and Whyte 1999) and in particular when patients are considered to be at the end of life and if identifiable risks are involved. However, these concerns apply across the board and are not particular to end-of-life research.

Question 4: Are There Additional Obligations and Responsibilities That Are Significantly Different for Researchers and Their Teams Working With These Populations?
Respect for persons continues to be a primary obligation of researchers dealing with populations at the end of life. A reason to institute special guidelines would be to require researchers to articulate the risks and benefits of their research given the current and future life circumstances facing potential participants and their families. This would be particularly important in those studies at the end of life, sometimes disdainfully referred to as "salvage studies." Here, patients' families and clinician researchers alike can get caught up in viewing the benefits of participation as holding out the only hope for survival. Guidelines might move IRBs to question studies where anticipated benefits are counted in weeks and could foster important discussion about whether participation in such studies might deprive patients and their families of their limited remaining time that might be better spent not involved in a research protocol. However, such guidelines would have the potential to promote an overly protective and paternalistic stance toward patients and families and do not afford opportunities for informed patients and their families to take their own risks and evaluate for themselves how they want to spend their last days.

	Summary

TOP Abstract Ethical Guidelines Doctrine of Informed Consent Vulnerable Patient Populations Investigators How Different Is End-of-Life... Are the Issues Sufficiently... Summary Directions for the Future References

 
Research at the end of life is diverse in methods, approaches, and goals and focuses on times that are inherently vulnerable for individuals coping with a disease and those in their lives. Arguments for imposing special requirements for research at the end of life focus on this vulnerability. Special requirements would help ensure that additional burdens are not placed on participants and a more focused review by IRBs. Arguments against special requirements focus on the need for ethical standards to apply across all research with human subjects. Special guidelines would create different standards for research that would be difficult to justify given both (a) the diversity of illnesses and their presentations that would make the parameters difficult to define and (b) the overarching need to have a cohesive set of guidelines and practices that can improve review of research with populations dealing with illness in general. Special requirements might also limit or restrict certain kinds of research with these populations, which with proper review and understandable informed consent processes, should be decided by decisionally capable persons themselves. Although there are important and compelling reasons why additional attention should be paid to research at the end of life, there are not enough to warrant special requirements.

Having argued against the need for special requirements, as have others (Casarett and Karlawish 2000), there is a need for more focused attention on the life circumstances of potential research subjects and those in their lives. In this regard, IRBs have an important role to play and need to review research at the end of life with consideration of the following: (a) The protocol clearly spells out the goals of the research and the presence or absence of benefits to be gained by the patient in terms of survival, life expectancy, or quality of life. (b) The methods of identifying patients do not violate ethical and legal standards regarding confidentiality and privacy. (c) The methods of assessing decision-making capacity are clearly defined, and the processes by which surrogates are to make decisions on behalf of the incapable patient are explained. There needs to be more explicit attention to the bases of both patient and surrogate views and delineation of an acceptable process for surrogate decision making. (d) The ability and skills of the research team to handle the emotional issues that may arise as a result of participating in the research are demonstrated. (e) Ongoing review could specifically ask about distress and burdens of the protocol to participants or surrogates, including more careful, ongoing monitoring of nonmedical reasons for (participants) dropping out of studies. (f) Views of potential benefit to be gained from participation should be refined on the basis of investigator experience and participant feedback. This knowledge will better inform our understanding of potential benefits from participating in research at the end of life and can be used to inform potential participants.

	Directions for the Future

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Although the question of guidelines provided the frame for this discussion, it is the individual research participant who provides us with directions for the future. To best evaluate whether current guidelines are meaningful, we need to know more about the experiences of these populations as they are approached and sometimes enroll in research. How and why do decisionally capable persons dealing with various eventually fatal illnesses decide to enroll in research? How do they compare with others in similar conditions who refuse enrollment? Do these populations view their rights and responsibilities as research participants differently from other research participants? Given that there may be "nothing to lose," do patients at the end of life evaluate risks and benefits differently from others? How do these responses vary between and among ethnically and culturally diverse groups? Most importantly, what can be learned about these differences that can be translated into improvements in care and caring at the end of life?

There are clearly important research questions about life's end, best models of care, variations in approaches, and disparities along the continuum of health and illness processes that are stimulating research efforts today. There are important assumptions about what individuals want and do not want that have not been tested with diverse populations. There are legal standards of decision making used when patients lose decision-making capacity; should they pertain to decisions about enrollment in research for patients who are unable to communicate their consent?

A consideration of whether special guidelines are needed is important because it draws attention to the life circumstances of research participants and our obligations as researchers to them. I have argued that they are not needed and would not improve the quality of ethics of research at the end of life. Nonetheless, it is essential that we as researchers and research bodies give careful examination to the dimensions discussed. This examination will greatly enhance the research endeavor and model the qualities for which end-of-life research should become known.

The Forum

Book Reviews

Practice Concepts

Received for publication October 2, 2001. Accepted for publication May 14, 2002.

	References

TOP Abstract Ethical Guidelines Doctrine of Informed Consent Vulnerable Patient Populations Investigators How Different Is End-of-Life... Are the Issues Sufficiently... Summary Directions for the Future References

 

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