Abstract
Abstract
Background:
Ethical concerns were identified as a potential barrier to advancing palliative and end-of-life science at the 2004 National Institutes of Health State of the Science Meeting. However, data are lacking about the nature of ethical concerns and strategies for balancing the need to advance science with human subjects protections.
Methods:
A qualitative case-study design was used to follow 43 end-of-life studies from proposal development through the review process and implementation. Investigators participated in semi-structured telephone interviews and provided document data regarding their experiences with grant and IRB reviews. Using constant comparative analysis within and across cases, the investigators identified commonly encountered and unique concerns and strategies for managing these concerns.
Findings:
Investigator strategies fell into two broad categories: 1) Recruitment and consent strategies related to subject identification and enrollment; and 2) Protocol-related strategies related to the process of data collection. These strategies shared the overarching meta-themes of compassion, as evidenced by a heightened sensitivity to the needs of the population, coupled with vigilance, as evidenced by close attention to the possible effects of study participation on the participants' well-being, clinical care, and the needs of research staff.
Conclusions:
Ethical concerns have led to the development of compassionate and vigilant strategies designed to balance the potential for risk of harm with the need to advance the science of palliative and end-of-life care. These strategies can be used by investigators to address ethical concerns and minimize barriers to the development of palliative and end-of-life care science.
Introduction
The Belmont Report principles of respect for persons (autonomy), beneficence, and justice offer a helpful framework for organizing these ethical concerns. 5 Autonomy-related concerns are focused on the ability to give informed consent. This raises questions about decisional capacity, assent, and proxy decision making.6,7 Of particular concern is whether individuals near the end of life are able to give voluntary consent to participation or whether they are overly susceptible to undue influence because of their poor health or dependence on treating clinicians.8,9 Beneficence-related concerns include questions about how to evaluate the risks of participation in palliative and end-of-life research as the risks and potential benefits related to participation may be different for someone who is healthy than for someone near the end of life.4,6,8,10 Although there may be no direct personal benefit, participants may still find meaning in the act of participating.11,12 Additionally, researchers need to ensure that clinical needs identified in the course of research are addressed.9,13,14 Justice-related issues include concerns that fair subject selection and equal opportunity to participate are not possible due to gatekeeping by organizations, clinicians, or family members, which limits investigators' ability to access potential subjects who may be interested in participation.2,15 Including populations with sensory, mobility, or cognitive impairments may necessitate adapting methods to accommodate disease-related limitations to ensure access. 16
There are minimal data available about how investigators manage the ethical challenges described above. The literature contains accounts of investigators' experiences with recruitment challenges in palliative and end-of-life care research that touch on ethical issues.15,17–20 However, only a few articles explicitly describe investigators' successful strategies for addressing ethical issues based on first-hand experiences with specific populations or settings.21–25 These articles make important contributions, but given the wide variations in institutional review board (IRB) evaluation of ethical issues, 26 there is a need for more systematic data about investigators' strategies across the full range of settings and populations where end-of-life research occurs.
Methods
A qualitative, exploratory case study design was used to identify and describe investigators' experiences conducting palliative and end-of-life care studies. Investigators were asked about all phases of the study including proposal submission, grant review, IRB review, and study implementation. Data sources included telephone interviews with the case study investigator as well as relevant document data (e.g., grant reviews, IRB correspondence). Following IRB approval, a certificate of confidentiality was obtained from the National Institutes of Health (NIH). Data collection occurred between August 2009 and July 2010. The focus of this paper is on strategies used to address ethical concerns raised by investigators, IRBs, and external reviewers.
Sample selection
Studies selected for potential inclusion were conducted in the U.S. and focused on social or behavioral issues related to terminally or seriously ill patients and/or their families. Studies with active funding were identified using the online NIH database and private foundation websites. Studies presented at professional conferences within the prior year were also eligible for inclusion. Studies were considered ineligible if data collection was completed before 2005. The search was narrowed using the same criteria used at the 2004 NIH State of the Science Consensus Conference on Improving Care of the Dying. 27 Case selection was guided by the principle of maximum variation to locate studies representing a range of funding sources, designs, methods, and participant populations. 28 The sample size was based on qualitative research sampling guidelines regarding scope of the study (focused) and nature of the topic (concrete), and interviews were continued until informational redundancy was achieved.29–31
Study procedures
Principal investigators were invited to participate by email. Investigators who agreed to be contacted were screened by phone to confirm case study eligibility. Telephone interviews were conducted by the study team (SH, JC, CN) using a semistructured, open-ended interview guide. Investigators were asked about their experiences with ethical issues during study development, funding, and implementation. Interviews lasted approximately an hour although several took close to two hours. Investigators were invited to submit relevant study documents pertaining to grant or IRB reviews. Interviews were transcribed verbatim, proofed for accuracy and removal of identifying information, and organized by study case using NVivo 8.0. 32
Analysis
Analysis was performed concurrently with data collection, and interview guides were modified based on ideas or questions that arose during the analysis. Well-established qualitative techniques guided analysis of the case data.33–35 Each case was analyzed using the following processes: open coding of interview data to inductively identify and label ideas or experiences, followed by examining the document data to locate additional ideas or information that elaborated on or confirmed what was discussed in the interview. Data were coded line by line. Where available, document data were used to confirm key ideas that emerged from the interview. After individual cases were coded, constant comparative analysis across cases was used to identify overarching themes and subthemes related to management strategies. 29 Themes were also compared for similarities and differences. Theoretical memos documented the types of strategies described by investigators. Demographic data about the participants were descriptively analyzed.
Verification of the analysis
To ensure consistency in coding the data, the research team developed a coding dictionary documenting code definitions and coding decisions related to the application of codes. Each interviewer separately coded the first 9 interview transcripts and then discussed differing coding interpretations with the team until consensus was reached. Following the identification of the initial code list, the remaining 34 transcripts were each coded by a primary and a secondary reviewer with discussions at regularly held team meetings. The code list continued to be refined during this process. The team met regularly with an expert methods consultant (KK) who audited the analytical procedures for overall quality.
Sample
Principal investigators for 74 case studies were contacted about participation: 43 (58.1%) agreed to participate; 9 (12.2%) actively refused to participate; 12 (16.2%) passively refused (by not responding to the invitation emails); and 10 (13.5%) were determined to be ineligible. Overall, 43/64 (62.7%) of eligible cases were included in the sample. For three studies, a second investigator also participated in the interview, resulting in a sample of 46 investigators sharing information about their experiences with 43 case studies (Tables 1 and 2).
In three instances a second investigator participated in the interview, but demographic data was only collected for the primary interviewee.
Strategies specific to palliative and end-of-life care research
The strategies described were largely developed by investigators either in anticipation of potential ethical concerns or as a result of prior research experiences. Few strategies were suggested by IRBs or external reviewers. More-junior investigators described the benefits of working with experts to learn relevant strategies; more-experienced investigators reported a process of building a collection of strategies over time. Table 3 contains a list of strategy categories with exemplar quotes and sample strategies used by investigators.
Recruitment and consent strategies
Consent to contact
Investigators reported that they were generally not allowed by IRBs to directly contact potential study participants “cold,” due to concerns about protecting patient confidentiality and a desire to avoid upsetting individuals during a sensitive time. Instead, the investigators had to develop strategies that gave potential participants the option to refuse any contact by the research team. Consent to contact was sometimes obtained by treating clinicians, an approach that protected confidentiality, allowed the clinical partners to confirm study eligibility, and made it possible to screen out individuals perceived to be too distressed to participate. However, clinicians who were unsupportive of the research did not always cooperate in identifying potential participants or presented the study only to a select (potentially biased) population of participants. In some situations, potential participants were sent a letter from either the investigator or a clinical partner indicating someone from the study would be in contact. Depending on the IRB, participants could either opt out of participation (by indicating they did not wish to be contacted) or opt in (meaning investigators were only able to call if the participant provided permission). Opt-outs were perceived as less burdensome for potential participants and more successful than opt-in strategies.
Initial contact
Investigators reported that the timing of the initial approach had to be carefully considered. In some cases this required the development of fairly broad eligibility criteria that allowed participants to decide when they felt ready to participate, even if it had been many months after the event under study (e.g., the death of a loved one). Investigators reported that they often employed multiple recruitment approaches within the same study, depending on the study site and other unique factors; and several described the importance of modifying recruitment strategies when accrual was slow. When a referral was received, a rapid response was often critical to avoid losing a potential subject due to declining health.
Consent process and forms
Whereas IRBs were perceived as emphasizing the use of standardized language and providing comprehensive details about risks and benefits in consent forms, investigators focused more on presenting information in ways that reduced burden, prevented distress, and fit the needs of a population already under duress. When possible, investigators obtained waivers of documentation of written consent from the IRB so that consent could be obtained verbally by phone or in person. Alternate versions of the consent form were provided by some investigators, such as a one-page summary or brochure that provided an overview of the study's purpose and what participation would entail. Several investigators described modifying the approach to obtaining consent so participants had the opportunity to ask questions about the study prior to enrollment (e.g., reading the consent form out loud at a deliberate, unhurried pace). Some obtained IRB approval for witnessed consent to help ensure physically impaired persons were able to participate even if they were unable to sign a form. Other investigators inserted language in the consent document describing the intent to report symptoms to clinicians in the event that clinical care was needed. A related strategy was providing examples of the most sensitive research questions in the consent form, so that participants who chose to consent were fully aware of the nature of the study questions.
Decisional capacity
Patients nearing the end of life may lack decisional capacity or may experience fluctuating and/or declining capacity. Investigators therefore stressed that it was important to have clear plans to assess capacity at the time of consent. In some studies, participants who lacked capacity were excluded from participation altogether. In other research it was important to include participants who lacked capacity to ensure the representativeness of the sample, as loss of capacity is common near the end of life. 36 For these studies, investigators described working with the IRB to determine who was viewed as an appropriate proxy and developing a plan to obtain assent either verbally or in writing from impaired participants. Investigators reported widely varied IRB policies about the participation of persons with decisional impairment, but in most settings, proxy consent was permitted by either a strictly defined legally authorized representative or a more loosely defined surrogate (such as a family member or domestic partner).
Protocol strategies
Approaching a potentially sensitive topic
Investigators described using a very active approach to data collection that involved constant monitoring and adjustment during data collection. The primary motivation behind this strategy was to be sensitive to the emotional needs of the patient or caregiver. This sensitivity included avoiding challenging the patient's understanding of his or her condition and caution about inadvertently imposing the investigator's values on the situation. Investigators described starting the survey or interview with nonthreatening topics to build trust and with probing questions to assess participants' willingness to engage in conversation about more sensitive topics such as diagnoses or prognoses. Interviews were diplomatically ended or specific items skipped if a participant signaled he or she was uncomfortable with the questions or was unwilling to respond. Other investigators described using very broad questions that allowed the participant to decide what if any aspects of the interview questions or survey items were relevant to their situation. Additional strategies included giving participants as much time as needed to reflect on emotional experiences both during and after the interview and concluding the interview with something more upbeat. Finally, some investigators reported that they reminded people frequently of their right to refuse to answer questions or to withdraw from the study at any time. For studies with more than one data collection time point, investigators described assigning the same team member to a participant for each time point to help build rapport as well as minimize the burden of getting used to a new person and style.
Use of language
Investigators considered the use of language to be very important in developing consent documents, recruitment materials, and data collection materials, and described numerous strategies to avoid inadvertently disclosing prognostic or diagnostic information to participants. These strategies included inserting language in the consent form or study materials indicating that “some of these questions may not apply to you” to allow participants who were troubled by certain words or phrases to maintain the belief that this language was not relevant to their situation. Investigators described “echoing” language, meaning they used certain terms and phrases only when first used by participants rather than risk using language that could be distressing. Specific terms that were commonly avoided in written materials and in conversation included “terminal,” “death,” “dying,” and “end of life.” More general terms such as “advanced illness,” “seriously ill,” “critically ill,” “life-threatening,” and “palliative care” were generally viewed as preferable, though there was no universal agreement about the acceptability of these terms. Some investigators reported that IRBs were not as sensitive about the use of language as they were themselves and provided examples of IRBs requiring the use of terms that investigators felt to be too direct and potentially upsetting.
Working with clinicians
Investigators who did data collection in clinical settings worked closely with the clinical team to avoid interfering with care and to ensure that physicians, nurses, and other members of the treatment team thought it was appropriate to approach patients for participation. In some situations, that meant postponing data collection based on either the clinician's opinion about the patient's ability to participate or on what was happening during that day's appointment.
Flexible methods
Being sensitive to the needs of participants required creativity and flexibility. Investigators reported being flexible about the timing of data collection or intervention based on the needs of the participant and careful tracking to ensure they avoided contacting participants on personally meaningful dates such as holidays, birthdays, or the date of death anniversary. Data collection time points were delayed or dropped if necessary to minimize burden despite the impact on scientific rigor. Missing data were dealt with in the analytic phase. In designing the study, investigators were careful to minimize the number, length, and complexity of instruments. Participants were allowed to decide whether they wished to be interviewed by phone or in person, whether they wished to read survey questions or have the items read out loud, where they preferred data collection to occur, and who they wanted in the room. Investigators described using real-time feedback to determine whether the participant was fatigued or upset, even if it resulted in terminating data collection prematurely.
Backup protocols
Investigators were very clear that they were engaging with participants as researchers rather than clinicians but described feeling a strong sense of responsibility to intervene when participants seemed to be emotionally or physically distressed. Backup protocols consisting of contingency plans for addressing participant distress were viewed favorably by most investigators and even required by some IRBs as an acceptable way to minimize risk. A backup protocol could be triggered when a study participant was observed to be in distress as a result of study participation (e.g., emotional distress) or due to an underlying, preexisting condition (e.g., untreated pain). The distress was recognized both through the use of objective “cut points” on study instruments and with more subjective observations. Some backup protocols involved asking the patient to share information with his or her clinician (for less urgent issues), notifying the participant's clinical care providers about the concern, providing a list of community resources, directly referring the patient to a resource such as mental health services, or delivering mental health services crisis intervention through experts affiliated with the research team. Confidentiality concerns were mitigated by notifying participants during the consent process about the existence of backup protocols. For many, the use of backup plans, such as reporting high levels of symptom distress in an observational study, represented a tradeoff with scientific rigor that was viewed as methodologically challenging but ethically necessary.
Research staff strategies
Many investigators expressed concerns that research with seriously ill and dying populations is challenging and emotionally laden. Therefore, hiring research staff who had previously worked with the study population in some capacity was highly valued. This helped ensure consent was sensitively obtained and it provided some reassurance that research staff had the necessary clinical expertise to be responsive to signs of distress. When it was not possible to hire staff with prior experience, investigators described careful training plans to develop the necessary skills. Additionally, investigators expressed concerns that it was not realistic to expect staff to fully understand the existential implications of doing research with seriously ill and dying populations, so applicants were carefully screened for their ability to manage stress. Investigators also described providing research staff with emotional support to help process their reactions to what they were hearing or observing during the course of data collection. When possible, more than one data collector was hired to provide a natural outlet for staff to informally share experiences. Strategies included encouraged research staff to journal and do additional reading about grief and bereavement; holding team meetings (including via phone for multisite studies) to process emotions and discuss challenging participants; including professional counselors in team meetings; referring to counselors for individual sessions; encouraging the use of alternative therapies for self-care; facilitating access to an expert consultant; and forming a project staff support group. In the best case scenario, funding was built into the study budget to provide some of these services.
Meta-themes
The strategies described above share the common, overarching meta-themes of compassion and vigilance. The concept of compassion was reflected in strategies that represented heightened sensitivity to the needs of the population such as allowing extra time to solicit consent, gently building up to sensitive questions, developing backup protocols, careful attention to the use of language, and methodological flexibility. Compassion was coupled with exercising heightened vigilance during every step of the research process about the possible effects of study participation on the participants' emotional and physical well-being, ensuring the research did not interfere with clinical care, and being attentive to the emotional needs of research staff. Investigators were fully committed to protecting human subjects and creative in the development of strategies to mitigate the potential risk of harm.
Discussion
Palliative and end-of-life investigators described a range of strategies sharing the underlying themes of compassion and vigilance that minimize ethical concerns in the course of recruiting, consenting, and conducting research with seriously ill patients and their family members. The strategies described by investigators reflect efforts to balance the principles of respect for patient autonomy, beneficence, and justice with the goal of minimizing negative outcomes related to research participation. 37
However, achieving a balance among these ethical principles often necessitates methodological and ethical tradeoffs. Most investigators reported that they obtained consent from treating clinicians prior to contacting potential participants, and several expressed the belief that this approach helps minimize the risk of harm and facilitates research by allowing clinicians to screen out patients who are too distressed or otherwise inappropriate for research. However, clinicians who are opposed to the research may act as gatekeepers and impede recruitment, limiting the applicability of study findings, or may leave patients feeling pressured to participate.7,15,37,38 Remaining flexible about study procedures allows investigators to meet the needs of seriously ill patients and potentially bereaved family members and increases opportunities for participation.6,37 However, being too flexible can result in a loss of generalizability and power, 15 which limits the value of the research.
Investigators proposing research with seriously ill patients and family members need to anticipate challenges such as these and proactively plan to minimize the impact of tradeoffs by building in procedures to reduce the effects of gatekeeping, developing alternative recruitment sites, crafting backup protocols to manage distressing symptoms, and devising plans for managing missing data. 6 If investigators are not attentive to these challenges in the course of the study design, it could impact the success of projects and ultimately raise concerns about the validity of this area of science. 7 These concerns also suggest it is important that IRB applications and grant proposals be reviewed by individuals with appropriate expertise who are able to evaluate whether proposed studies are both sensitive to the needs of the population and address potential methodological limitations that could impact the usefulness of study findings.
A key limitation of this study is that the findings represent only the experiences of those investigators who agreed to be interviewed. Although efforts were made to include research that reflected a broad array of end-of-life and palliative care issues, the experiences and perceptions of the study participants may be different from those of people not invited or unwilling to participate in the study. Additionally, the investigators who were interviewed were on average a highly experienced group of researchers who developed strategies over time through a program of research, and newer investigators may not be as adept at managing ethical concerns.
Findings suggest that investigators who do research with seriously ill patients and family members are creative in managing ethical concerns through compassionate and vigilant strategies. The identification of commonly used, successful strategies may be useful in developing evidence-based standards for evaluating research with palliative and end-of-life care populations. Although IRBs vary in their interpretation of federal policy for the protection of human subjects and the Health Insurance Portability and Accountability Act of 1996 (HIPAA), many of these strategies can be adapted to fit local conditions in order to address ethical concerns and minimize barriers to the development of palliative and end-of-life care science.
Footnotes
Acknowledgments
We are enormously grateful to the generous investigators who shared their time and knowledge with us for the purposes of this study. We also thank our collaborator Susan B. Bankowski, J.D., M.S., who was a valuable collaborator in the development of the research grant that supported this study. Finally, we are appreciative of suggestions of our expert consultants Charles F. von Gunten, M.D., Ph.D., and Jeremy Sugarman, M.D., M.P.H., M.A., who helped us in revising our interview guide and identifying preliminary themes in the data. This study was supported by a grant from the National Institute of Nursing Research (NR010397).
Author Disclosure Statement
The authors report no financial conflicts of interest.