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Parents' views of their children's participation in phase I oncology clinical trials
Parents’ Views of their Children’s Participation in Phase I Oncology Clinical Trials Janet A. Deatrick, PhD, FAAN, Denise B. Angst, DNSc, and Carol Moore, MSN, CRNP Data from two descriptive studies regarding decision making in pediatric oncology were analyzed using qualitative, secondary analysis techniques to describe how parents view their children’s participation in phase I oncology clinical trials. A conceptual framework on family management styles (defining, managing, and consequence themes) was used as an organizational framework to analyze the available parental data. Parents defined or viewed their situation in relationship to their choices and expectations, health care provider expectations, children’s illness situation, and family and personal situations. These themes are contrasted to clinical, parental, and ethical perspectives from the literature to make recommendations for further research emphasizing the concerns of families. 䊚 2002 by Association of Pediatric Oncology Nurses
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HE National Institutes of Health and the Federal Food and Drug Administration now require children to be included in all human subjects research conducted or funded by these agencies unless scientific or ethical reasons preclude them from being included. Participation of children in research, however, raises complex social, psychological, physical, ethical, From the International Center of Research for Women, Children, and Families, University of Pennsylvania School of Nursing, Philadelphia, PA; Lutheran General Children’s Hospital, Park Ridge, IL; Bloomsburg University, Bloomsburg, PA. Address reprint requests to Janet A. Deatrick, PhD, FAAN, Associate Professor and Co-Director, International Center of Research for Women, Children, and Families, University of Pennsylvania School of Nursing, 420 Guardian Drive, Philadelphia, PA 19104-6096. E-mail: [email protected] The analysis reported in this manuscript was funded by a grant from The Serious Illness Center, University of Pennsylvania, to Dr. Janet A. Deatrick. The original study was supported in part by a grant from Project on Death in America (principal investigator: Dr. Pam Hinds), the American Association of Critical Care Nurses, and by a Cancer Center Support CORE Grant, P30 CA21765 award, to St. Jude Children’s Research Hospital and the American Lebanese Syrian Associated Charities. The authors of this study thank the patients, families, and staff of St. Jude Children’s Research Hospital and especially to the nursing research team at St. Jude headed by Dr. Pam Hinds. © 2002 by Association of Pediatric Oncology Nurses 1043-4542/02/1904-0002$35.00/0 doi:10.1053/jpon.2002.126057 114
and regulatory concerns for children and their families (Adamson & Starr, 2001). This is especially true of children’s participation in phase I clinical trials in which direct benefits to subjects is unlikely and in which child assent to treatment is very complicated (American Society of Clinical Oncology, 1997). Although we do have some knowledge related to how adults make decisions about their own health care (Denger, 1998; Pierce & Hicks, 2001) and how professionals (Estlin, Cotterill, Pratt, Pearson, & Bernstein, 2000; Kodish, Stocking, Ratain, Kohrman, & Siegler, 1992) and family members define, manage, and evaluate children’s participation in research (Broome, Richards, & Hall, 2001; Hall, Stevens, & Pletsch, 2001; Liaschenko & Underwood, 2001; Pletsch & Stevens, 2001; Snethen & Broome, 2001), we know little about family decision making regarding children’s participation in phase I clinical trials (Hinds et al., 1998a). Children with cancer may become candidates for phase I clinical trials when all other treatment has failed or when no available established treatment exists. No likelihood of direct benefit exists in terms of the children’s cancer; parents and children may hope that the trial will pro-
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long life. Phase I oncology clinical trials investigate dose-limiting toxicity and detect maximum-tolerated doses (MTD) for a given schedule and dose (American Society of Clinical Oncology, 1997; Eisenhauer, O’Dwyer, Christian, & Humphrey, 2000). Because there are often insufficient numbers of pediatric patients to permit dose escalation along the entire dosetoxicity curve, the common practice is to start at 80% MTD and escalate by 30%, thus minimizing the number of children needed for study and assuring that children would receive a dose that is biologically active (Smith et al., 1998). Phase 2 trials are done to test the activity against individual tumor types. Phase 3 trials test the activity of the protocol in comparative fashion relative to the natural history of the disease and standard therapy. Phase 4 trials test the feasibility of delivering the treatment to the public (Ungerleider & Ellenberg, 1993). With each phase of the trial, the protocol must be designed to assure equipoise, meaning that there is a reasonable likelihood of success for various treatments (Alderson, 1996). The scientific community justifies the importance of children’s inclusion in clinical research in terms of the need for empirical data about the safety and efficacy of treatments for children. We need to understand parent and child perceptions about their participation to strengthen mechanisms to assure informed consent and the appropriate conduct of trials involving children generally and those with life-threatening conditions in particular. Although the literature clearly contains clinical and philosophic perspectives on these issues, the perspectives of parents and child subjects are largely absent. The purpose of this study is to describe parents’ views about their children’s participation in phase I oncology clinical trials.
recipients. Broome, et al. (2001); Hall, Stevens, and Pletsch (2001); Liaschenko and Underwood (2001); Pletsch and Stevens (2001); and Snethen and Broome (2001b) explored participants’ ethical concerns, the process and meaning of informed consent, their understanding of clinical research, and the sociocultural and structural factors that influence the process. Understanding of the research was influenced by the illness itself and the need for the investigational treatment. Parents of children with cancer had the greatest difficulties distinguishing the lines between treatment and research and saw little choice regarding participation. In contrast, those parents of children with diabetes were able to make a more accurate distinction and perceived a choice in the decision making. Hinds and colleagues (1997a, 2001a, 2001b) have found similar results in studies of children with cancer. Retrospective interviews with parents revealed that they experienced great difficulty in deciding between a phase I trial and no further treatment, and most were influenced by the recommendations of health professionals. Prospective interviews with parents revealed that being supported by staff was also the most important factor across all decision types. In phase I decisions, choosing options that could benefit their children and selecting options of less toxicity were most important. Although we have learned about how family members may view participation of their children in research, we know little about how parents may prospectively describe their perceptions about their children’s participation in phase I clinical trials. The study reported in this article extends our understanding, providing an in-depth description of the perceptions of parents who decided to have their children participate in phase I clinical trials.
Background
Conceptual Framework
The perspectives of individual family members about children’s involvement in clinical research are described in the literature (Wiley et al., 1999). In the most comprehensive study to date, Broome and colleagues studied the experience of parents, siblings, and children (ages 9 to 18 years) with diabetes, cancer, or sickle cell disease or who were bone marrow transplant
Family management styles (FMS) were chosen to organize the perspectives of the various family members in terms of the defining (views/ perceptions), management, and consequence themes (Knafl & Deatrick, 1990) because these styles systematically sensitize the data analyst to take into account the multifaceted nature of the family situation. Family is defined as the child,
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the parents who are legally sanctioned to give consent for treatment, and other individuals, except staff members, who may influence the process.
Methods This descriptive, cross-sectional study used secondary analysis techniques to analyze existing qualitative data from two studies of parents’ decision making at end of life for their children with cancer. The setting for the primary two studies was a children’s cancer research center in the Midsouth. Both studies were based on the initial phase of a decision-making model, which involves characterizing the process of decision making (Hinds et al., 1998b). The first study was a retrospective study of 39 English-speaking parents of children (Hinds et al., 1998c). Interviews were based on a 5-item structured interview format and a 15-item multiple-choice questionnaire. The second study is a prospective study of 52 parents, 10 adolescents, and 22 physicians who were interviewed during end-of-life decisions and used methods refined in the first study (Hinds et al., 1998b; 2001a, 2001b). Subject and Child Characteristics A subset of parents’ transcripts from Hinds and colleagues’ prospective or retrospective studies that contained data concerning consideration of phase I clinical trials was analyzed for this study. All cases (n ⫽ 21; 19 mothers, 2 fathers) were in the prospective study. Children were between 2 and 18 years of age. Eleven children were male and 10 were female. The majority of children were either white (12; 57%) or black (7; 33%). The children were diagnosed with solid tumors (15; 72%); leukemias (3; 14%); and, other malignancies (3; 14%). All were interviewed within 7 days from the decision to participate in the phase I clinical trial.
Data Management and Analysis The investigators used qualitative, secondary analysis techniques to analyze the data (Hinds et al., 1997b; Santacroce, Deatrick, & Ledlie, 2000). Consistent with the FMS model, findings
were organized around parents’ views, management, and satisfaction with their participation. This article describes parents’ view of their participation with other results related to management (Angst, Deatrick, & Murphy-Moore, in progress) and spirituality (Murphy-Moore, Angst, & Deatrick, in progress), reported elsewhere. Access to the transcripts, demographic data, and Institutional Review Board (IRB) documents was successfully negotiated with Hinds and colleagues. IRB approval for this analysis was secured from the institution of the first author. No additional consent was needed from the parents because the original consent was sufficiently broad to accommodate the research questions for this study. Two of the investigators (JD, DA) read a complete set of the transcripts. First, themes in the data were identified in the transcripts of four subjects recorded in a case summary completed by each investigator. Second, through series of communications between the investigators, themes were consolidated and further defined. Third, the transcripts from the other 17 subjects were divided among the investigators for analysis and for preparation of case summaries and identified themes. The investigators also highlighted illustrative quotations in each transcript. Fourth, the investigators collaboratively prepared a summary of themes across all 21 cases, revising the themes as new insights developed. Fifth, support and understanding concerning each theme was sought in the literature. Criteria and procedures to strengthen the integrity of this analysis established by Hinds, Vogel, and Clarke-Steffen (1997b) and later described by Santacroce et al., (2000) were used in this analysis. A “pretest” using these criteria was completed with four transcripts by two of the investigators (JD, DA) to judge the quality of the data. The data set was judged favorably given: (1) the investigators had access to the research team and the data; (2) the data set was judged to be complete; (3) the data contained in the data set were of sufficient quality, completeness, and currency, and fit with the secondary research question; and (4) the primary research team was educationally and experientially expert.
Phase I Clinical Trials
Results Parents defined or viewed their situation in relation to their view of choice in the decision making, their expectations of the treatment, their interactions with health care providers, their children’s illness situation, and family considerations. Parental Themes Choices. All parents saw limited choices or no choice in the decision about whether to enter their children in a phase I clinical trial. Thirteen of the parents said that they did not have any choice in their situation. They knew that they signed a consent form, but, they didn’t think of it as a decision. There was no choice. . .It was just either this or we can’t treat you. I mean, it was definite. You either do this or there’s nothing we can do for you.
These parents described “choice” in terms of the promise of potentially “curative” treatment, not in terms of providing comfort or palliation. Eight parents acknowledged alternatives to trial participation, but did not feel that they had a choice. Because other treatments had already been exhausted, they could not deny participation in the trial if they wanted to continue “the fight.” As one parent remarked, There wasn’t really a choice in my mind because if I chose to not do anything then I would have been choosing to let her go and I’m not ready for that.
These parents described their situation as making a choice between participating in this clinical trial or doing “nothing.” Whether they thought a choice existed or not, parents described a range of reactions to the “decision,” from automatic to agonized, including one parent who stated, It’s like we’re going to do whatever we can to try and help her. . .I didn’t have to study on it or think about it hard. All I had to do was look at her and see how bad the pain she was in. They said there was a possibility this could help.
Expectations. Parents voiced a variety of expectations of the trial. These included providing treatment, buying time for another therapy, working a miracle, being altruistic, and delaying death.
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Most parents saw their child’s participation in the trial as a means of providing treatment to prolong life, through an uncertain treatment. Many parents had no idea if the treatment provided by the phase I agent would help or not, saying, “I don’t know which way we are going here.” Other parents began to question their decisions as they saw their children decline or saw little benefit from the trial agent. By trying this new drug, I’m still fighting the keep her here with me. . .I am beginning to know that may not happen.
One particular group of parents who wanted to prolong the lives of their children did so for a very specific reason. The phase I trial was a means to another end. That is, they were buying time for another therapy such as another clinical trial, tumor vaccine, or transplant: We had a child to store the cord blood and we are looking for a place now who can do cord blood transplants, which is one reason we are interested in the phase I treatment to put him into remission state, so that the cord blood transplant could be performed and possibly save our son’s life.
Some parents clearly emphasized the trial was a means to delaying their children’s death. Although related to the theme of “prolonging life,” this mother’s language about losing her daughter is certainly different: . . .If it did not [work], I want to say we tried. I keep thinking about losing her; it is the only thing I can think about.
Some parents were hoping for a cure or a miracle, whereas others stated that this was not their expectation. Many admitted that they wanted a miracle, but that they might not get one. Expectations about the efficacy of the proposed treatment were developed around many criteria, such as the occurrence of side effects, how others in the trial responded, and the mechanism of action and odds of success in relationship to the child’s previous treatments: This is my daughter’s second phase I study. The first one did not help; I know other children treated with this protocol that did well.
The desire to help other children with cancer in the future was evident in the altruistic expectations of some parents:
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We know the cancer he has is almost impossible to treat at this point and all we can do is hope for some miracle somewhere. Whether this works or not, we decided that it was just a chance. If nothing else, it will help somebody else down the road.
Another parent had a more complex altruistic motive that was mingled with the knowledge of family needs: . . .We feel that if he would die in a useful manner, it would kind of help cleanse us of the burden. . .give it a little bit of meaning. . .Whereas going home and dying on the bed to us is very meaningless and very frustrating, and just very damaging in every sense of the word. . .It’s family dealing with death in a very real [way]. . .At least we have made the effort. . .and enhanced some type of ongoing study. . .that would be my son’s legacy.
Interactions with health care providers. As families faced the option of phase I trial participation, health care providers provided information, concern, and alternatives. Parents discussed how physicians expressed concern about their children and helped them make the best decision. One parent stated: The thing that helped was the way he [the doctor] just had the confidence that this was a good drug for her. He let me know that it was still in study, but, he was very optimistic about it and he wanted to try it on her. I guess it was the way he presented it to me that was the deciding factor.
When health care providers demonstrated openness and presented options these were praised by parents. Parents clearly wanted information to help them problem solve. For instance, one provider explained which clinical trials could be tried first that would not limit options, that is, they had different eligibility criteria and could be sequenced to increased options. Some parents wanted more direction than others. They knew, however, that health care providers could not tell them whether they had made the “right” choice: What made it so hard for me is that I’m not a doctor, and he was so well-educated. He usually guides me well with decisions, but he couldn’t tell me what to do here, and it made me feel so helpless. . .I wanted so much to have someone else tell me that I had made the right decision, but there isn’t anyone who can tell me that.
Illness situation. The parents described their overall state of affairs in terms of their child’s
overall illness experience, the immediacy of the decision, and by efforts to keep trying. The children all had advanced cancer and had no aggressive treatment alternatives other than the phase I clinical trial. Parents knew that they had to make a decision quickly, otherwise death was imminent. Some parents said that they would bear tremendous guilt if they did not try the phase I trial. Others defined participation in the phase I trial as the only way to “keep trying” with a treatment that may or may not work. As one parent said, “You have to try everything. . .keep fighting to keep her here with me. You have to do what you have to do.” On some level, every one of the 21 parents continued to view their role as parent and their human need to keep trying: He [the doctor] didn’t give me that option [of stopping therapy]. I asked him if this was a last chance (crying) and he said he wouldn’t let it be.
Family considerations. Parental circumstances also played a role in how they viewed their children’s participation in phase I clinical trials, including practical issues, children’s capacity, and spirituality. Parents, in part, chose this treatment because of practical concerns including the location and the proximity of available treatment, ability to secure the treatment in the near future (time concerns), and issues that can be broadly defined as quality of life (e.g., amount of hospitalization, hair loss, vomiting). One family choose a particular phase I trial over another because the child could stay in an institution where he was comfortable. The parents commented that their son was characteristically not good at making change anyway, so changing institutions for an unknown treatment did not seem wise. For two families timing was an important issue in their decision. They could get into a trial right now in their present treatment facility and if that trial failed, they could go to the other institution as backup. Parents like this one also considered their children’s’ immediate needs and capacities: He was going to have to start a therapy and we want it to be the easiest thing for him, with the best results, which is a very fine line that you are walking.
The children’s capacity was described in terms of characteristics that bolstered parents’ decisions:
Phase I Clinical Trials She is a trooper. . . fighter. She does not give up. She was given 3-5 months to live, almost 2 years ago. She has a lot of faith. She kept telling me that she isn’t going to die.
Other parents variously described how their children’s physical condition, (e.g., good shape, weak) influenced their “decision.” Past or present child strength or resiliency influenced parents’ decision to choose trial participation. As one parent explained: We feel strongly that we are going to pursue any avenue at this point. . .as a matter of fact, probably the opposite of most parents who don’t want to see their kids suffer any more. We would rather see him go through a protocol with the hopes of getting some results than not. Because he is in very good shape. He is a pretty strong kid.
Spirituality was also central to many of the parents and is being described in another manuscript (Murphy-Moore, Angst, & Deatrick, in progress).
Discussion Study of phase III trials by Broome, et al. (2001b); Hall, Stevens, and Pletsch (2001); Liaschenko and Underwood (2001); Pletsch and Stevens (2001); and Snethen and Broome (2001) found that parents of children with cancer largely saw no “choice” in decisions around trial participation. Similarly, in this study of phase I trials, parents also saw little to no choice. Parents’ perceptions of “benefit” for these two groups were likely different, although their situations were similar; namely, an unfamiliar and devastating disease called childhood cancer. Benefit as traditionally defined would be more consistent with the situation of parents whose children are in phase III trials. Ethicists may ask philosophic questions, including concerns about the voluntariness (President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1983) of parents’ decisions. Nelson and Rushton (2001) point out in their commentary of Broome’s study (2001a) that the subjects who blurred the line between research and treatment further emphasized the view that there was no choice but to pursue anything that is offered as a chance of survival. They further
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point out that a forced choice appears to diminish viable courses of action and to undercut the possibility of informed and voluntary consent. They conclude that those parents in Broome’s study (2001a) whose children were in need of a bone marrow transplant for treatment of cancer (phase III clinical trial) experienced a situation of limited choice but could give voluntary and informed assent/ permission in this situation. The American Society of Clinical Oncology (1997) states that participation of individuals with advanced cancer in phase I trials is ethically questionable to the extent that the “vulnerable” population does not know that they are going to die from their disease. They also cautioned that patients whose death is imminent might not be capable of analyzing risks of participation. When did the parents in this study consider that death was imminent? Parents stress a relational and collaborative, informed (child and health care provider) paradigm when making health care choices (Kirshbaum, 1996; Pike-Grimm, Degner, Small, & Mueller, 1999; Rushton, 1994). That is, they would like us to ask, what does it mean to you to be a good parent in this situation? Health care providers stress a decisional paradigm and would most likely ask in this situation, do you want to do this treatment for your child? When would parents say yes or no to this question (Kodish, Stocking, Ratain, Kohrman, & Siegler, 1992; Estlin, Cotterill, Pratt, Pearson, & Bernstein; 2000)? Whatever the answers to these questions, we know that parental, ethical, and clinical perspectives are different. Only further research will help ascertain how these diverse perspectives may or may not be complementary. Hinds and colleagues (1997a) found that the majority of the hardest decisions for parents whose children had died were those decisions around end-of-life care rather than those about “treatment.” The secondary analysis reported in this article did not put this decision into the context of the families’ overall view of end-oflife questions and issues. As a secondary analysis of parental cases in a study coded during the primary analysis to include parental themes regarding phase I clinical trials, 19 mothers and 2 fathers were included. The study was focused on their perceptions. The intent of the study was
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neither to describe the perceptions of the family as a whole, nor to ascertain their views about other members of the family who were not being interviewed. Future studies conceptualized and implemented as family research can prospectively gather data on these issues. For instance, Norton and Bowers (2001) recently identified helpful health care provider strategies in adult end-of-
life situations. They creatively enable the reader to understand strategies providers successfully used to help families shift their perspectives to the “big picture” regarding end-of-life and palliative care. Through such studies that systematically conceptualize the patients, families, and providers’ perspectives, we will better understand these situations, which are the heart and soul of nursing practice.
References Adamson, P.C., & Starr, S. E. (2001). Pediatric clinical trials: Design and performance. Research and Practice, 1(1), 41-47. American Society of Clinical Oncology. (1997). Critical role of Phase I clinical trials in cancer treatment. Journal of Clinical Oncology, 15(2), 853-859. Broome, M. E. (2001a). Response: A different type of classroom— on leading and learning. Journal of Family Nursing, 7(7), 214-218. Broome, M. E., Richards, D. J., & Hall, J. M. (2001b). Children in research: The experience of ill children and adolescents. Journal of Family Nursing, 7(1), 32-49. Denger, L. (1998). Preferences to participate in treatment decision-making: The adult model. Journal of Pediatric Oncology Nursing, 15(3), 3-9. Eisenhauer, E. A., O’Dwyer, P. J., Christian, M., & Humphrey. (2000). Phase I clinical trial design in cancer drug development. Journal of Clinical Oncology, 18(3), 684-692. Estlin, E. J., Cotterill, S., Pratt, C. B., Pearson, A. D. J., & Bernstein, M. (2000). Phase I trials in pediatric oncology: Perceptions of pediatricians from the United Kingdom Children’s Cancer Study Group and the Pediatric Oncology Group. Journal of Clinical Oncology, 18(9), 1900-1905. Hall, J. M., Stevens, P. E., & Pletsch, P. K. (2001). Team research using qualitative methods: Investigating children’s involvement in clinical research. Journal of Family Nursing, 7(1), 7-31. Hinds, P., Drew, D., DeSwart-Wallis, J., Gibson, F., Hollen, P., Hunt, J. et al. (1998a). Consensus statement: Decision making in pediatric oncology. Journal of Pediatric Oncology Nursing, 15(3, suppl 1), 24. Hinds, P., Oakes, L., & Furman, W. (2001a). End of life decision-making in pediatric oncology. In B. Ferrell & N. Coyle (Eds.). Oxford textbook of palliative care. New York: Oxford University Press. Hinds, P., Oakes, L., Furman, W., Foppiano, P., Olson, M. S., Quargnenti, A., et al. (1997a). Decision making by parents and healthcare professionals when considering continued care for pediatric patients with cancer. Oncology Nursing Forum, 24(9), 1523-1528. Hinds, P., Oakes, L., Furman, W., Quargnenti, A., Olson, M. S., Foppiano, P., & Srivastava, D. K. (2001b). End-of-life decision making by adolescents, parents, and healthcare providers in pediatric oncology. Cancer Nursing, 24(2), 122136. Hinds, P., Oakes, L., Quargnenti, A., Furman, W., Sandlund, J., Bowman, L., et al. (1998c). Treatment decision
making for pediatric oncology patients by their parents and healthcare professionals. Funded by the Association of Critical Care Nurses. Hinds, P., Oakes, L., Quargnenti, A., Furman, W., Sandlund, J. T., Bowman, L., et al. (1998b). Challenges and issues in conducting descriptive decision-making in pediatric oncology: A tale of two studies. Journal of Pediatric Oncology Nursing, 15(3, suppl 1), 10-17. Hinds, P., Votel, R., & Clarke-Steffen, L. (1997b). The possibilities and pitfalls of doing a secondary analysis of a qualitative data set. Qualitative Health Research, 7(3), 408-424. Kirschbaum, M. (1996) Life support decisions for children: What do parents value? Advances in Nursing Science, 19(1), 51-71. Knafl, K., & Deatrick, J. (1990). Family management style: Concept analysis and development. Journal of Pediatric Nursing, 5(1), 209-214. Kodish, E., Stocking, C., Ratain, M. J., Kohrman, A., & Siegler, M. (1992). Ethical issues in phase I oncology research: A comparison of investigators and institutional review board chairpersons. Journal of Clinical Oncology, 10(11), 1810-1816. Liaschenko, J. & Underwood, S. M. (2001). Children in research: Fathers in cancer research—meanings and reasons for participation. Journal of Family Nursing, 7(1), 71-91. Nelson, R. M., & Rushton, C. H. (2001). Commentary on special issue on informed consent with families of ill children: Understanding devastation and difference in informed permission and assent. Journal of Family Nursing, 7(1), 208213. Norton, S., & Bowers, B. (2001). Working toward a consensus: Providers’ strategies to shift patients from curative to palliative treatment choices. Research in Nursing & Health, 24, 258-269. Pierce, P., & Hicks, F. (2001). Patient decision-making behavior: An emerging paradigm for nursing science. Nursing Research, 50(5), 267-274. Pike-Grimm, K., Degner, L., Small, A., & Mueller, B. (1999). Preferences for participation in treatment decisionmaking and information needs of parents of children with cancer: A pilot study. Journal of Pediatric Oncology Nursing, 16(1), 13-24. Pletsch, P. M., & Stevens, P. E. (2001). Children in research: Informed consent and critical factors affecting mothers. Journal of Family Nursing, 7(1), 50-70. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research.
Phase I Clinical Trials (1983). Deciding to forego life-sustaining treatment. Washington, DC: U.S. Government Printing Office. Rushton, C. (1994). Ethical decision-making: The role of parents. Capsules and Comments in Pediatric Nursing, 1(2), 1-10. Santacroce, S., Deatrick, J., & Ledlie, S. (May/June 2000). Secondary analysis of qualitative data: A means of collaboration in HIV-related research. Journal of the Association of Nurses in AIDS Care, 11(3), 99-104. Smith, M., Bernstein, M., Bleyer, W., Borsi, J., Ho, P.,
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Lewis, I., et al. (1998). Conduct of phase I trials in children with cancer. Journal of Clinical Oncology, 16(3), 966-978. Snethen, J. A., & Broome, M. E. (2001). Children in research: The experiences of siblings in research is a family affair. Journal of Family Nursing, 7(1), 92-110. Wiley, F., Ruccione, K., Moore, I., McGuire-Cullen, P., Fergusson, J., Waskerwitz, M., et al. (1999). Parents’ perceptions of randomized pediatric clinical trials. Cancer Practice, 7(5), 248-256.
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HE National Institutes of Health and the Federal Food and Drug Administration now require children to be included in all human subjects research conducted or funded by these agencies unless scientific or ethical reasons preclude them from being included. Participation of children in research, however, raises complex social, psychological, physical, ethical, From the International Center of Research for Women, Children, and Families, University of Pennsylvania School of Nursing, Philadelphia, PA; Lutheran General Children’s Hospital, Park Ridge, IL; Bloomsburg University, Bloomsburg, PA. Address reprint requests to Janet A. Deatrick, PhD, FAAN, Associate Professor and Co-Director, International Center of Research for Women, Children, and Families, University of Pennsylvania School of Nursing, 420 Guardian Drive, Philadelphia, PA 19104-6096. E-mail: [email protected] The analysis reported in this manuscript was funded by a grant from The Serious Illness Center, University of Pennsylvania, to Dr. Janet A. Deatrick. The original study was supported in part by a grant from Project on Death in America (principal investigator: Dr. Pam Hinds), the American Association of Critical Care Nurses, and by a Cancer Center Support CORE Grant, P30 CA21765 award, to St. Jude Children’s Research Hospital and the American Lebanese Syrian Associated Charities. The authors of this study thank the patients, families, and staff of St. Jude Children’s Research Hospital and especially to the nursing research team at St. Jude headed by Dr. Pam Hinds. © 2002 by Association of Pediatric Oncology Nurses 1043-4542/02/1904-0002$35.00/0 doi:10.1053/jpon.2002.126057 114
and regulatory concerns for children and their families (Adamson & Starr, 2001). This is especially true of children’s participation in phase I clinical trials in which direct benefits to subjects is unlikely and in which child assent to treatment is very complicated (American Society of Clinical Oncology, 1997). Although we do have some knowledge related to how adults make decisions about their own health care (Denger, 1998; Pierce & Hicks, 2001) and how professionals (Estlin, Cotterill, Pratt, Pearson, & Bernstein, 2000; Kodish, Stocking, Ratain, Kohrman, & Siegler, 1992) and family members define, manage, and evaluate children’s participation in research (Broome, Richards, & Hall, 2001; Hall, Stevens, & Pletsch, 2001; Liaschenko & Underwood, 2001; Pletsch & Stevens, 2001; Snethen & Broome, 2001), we know little about family decision making regarding children’s participation in phase I clinical trials (Hinds et al., 1998a). Children with cancer may become candidates for phase I clinical trials when all other treatment has failed or when no available established treatment exists. No likelihood of direct benefit exists in terms of the children’s cancer; parents and children may hope that the trial will pro-
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long life. Phase I oncology clinical trials investigate dose-limiting toxicity and detect maximum-tolerated doses (MTD) for a given schedule and dose (American Society of Clinical Oncology, 1997; Eisenhauer, O’Dwyer, Christian, & Humphrey, 2000). Because there are often insufficient numbers of pediatric patients to permit dose escalation along the entire dosetoxicity curve, the common practice is to start at 80% MTD and escalate by 30%, thus minimizing the number of children needed for study and assuring that children would receive a dose that is biologically active (Smith et al., 1998). Phase 2 trials are done to test the activity against individual tumor types. Phase 3 trials test the activity of the protocol in comparative fashion relative to the natural history of the disease and standard therapy. Phase 4 trials test the feasibility of delivering the treatment to the public (Ungerleider & Ellenberg, 1993). With each phase of the trial, the protocol must be designed to assure equipoise, meaning that there is a reasonable likelihood of success for various treatments (Alderson, 1996). The scientific community justifies the importance of children’s inclusion in clinical research in terms of the need for empirical data about the safety and efficacy of treatments for children. We need to understand parent and child perceptions about their participation to strengthen mechanisms to assure informed consent and the appropriate conduct of trials involving children generally and those with life-threatening conditions in particular. Although the literature clearly contains clinical and philosophic perspectives on these issues, the perspectives of parents and child subjects are largely absent. The purpose of this study is to describe parents’ views about their children’s participation in phase I oncology clinical trials.
recipients. Broome, et al. (2001); Hall, Stevens, and Pletsch (2001); Liaschenko and Underwood (2001); Pletsch and Stevens (2001); and Snethen and Broome (2001b) explored participants’ ethical concerns, the process and meaning of informed consent, their understanding of clinical research, and the sociocultural and structural factors that influence the process. Understanding of the research was influenced by the illness itself and the need for the investigational treatment. Parents of children with cancer had the greatest difficulties distinguishing the lines between treatment and research and saw little choice regarding participation. In contrast, those parents of children with diabetes were able to make a more accurate distinction and perceived a choice in the decision making. Hinds and colleagues (1997a, 2001a, 2001b) have found similar results in studies of children with cancer. Retrospective interviews with parents revealed that they experienced great difficulty in deciding between a phase I trial and no further treatment, and most were influenced by the recommendations of health professionals. Prospective interviews with parents revealed that being supported by staff was also the most important factor across all decision types. In phase I decisions, choosing options that could benefit their children and selecting options of less toxicity were most important. Although we have learned about how family members may view participation of their children in research, we know little about how parents may prospectively describe their perceptions about their children’s participation in phase I clinical trials. The study reported in this article extends our understanding, providing an in-depth description of the perceptions of parents who decided to have their children participate in phase I clinical trials.
Background
Conceptual Framework
The perspectives of individual family members about children’s involvement in clinical research are described in the literature (Wiley et al., 1999). In the most comprehensive study to date, Broome and colleagues studied the experience of parents, siblings, and children (ages 9 to 18 years) with diabetes, cancer, or sickle cell disease or who were bone marrow transplant
Family management styles (FMS) were chosen to organize the perspectives of the various family members in terms of the defining (views/ perceptions), management, and consequence themes (Knafl & Deatrick, 1990) because these styles systematically sensitize the data analyst to take into account the multifaceted nature of the family situation. Family is defined as the child,
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the parents who are legally sanctioned to give consent for treatment, and other individuals, except staff members, who may influence the process.
Methods This descriptive, cross-sectional study used secondary analysis techniques to analyze existing qualitative data from two studies of parents’ decision making at end of life for their children with cancer. The setting for the primary two studies was a children’s cancer research center in the Midsouth. Both studies were based on the initial phase of a decision-making model, which involves characterizing the process of decision making (Hinds et al., 1998b). The first study was a retrospective study of 39 English-speaking parents of children (Hinds et al., 1998c). Interviews were based on a 5-item structured interview format and a 15-item multiple-choice questionnaire. The second study is a prospective study of 52 parents, 10 adolescents, and 22 physicians who were interviewed during end-of-life decisions and used methods refined in the first study (Hinds et al., 1998b; 2001a, 2001b). Subject and Child Characteristics A subset of parents’ transcripts from Hinds and colleagues’ prospective or retrospective studies that contained data concerning consideration of phase I clinical trials was analyzed for this study. All cases (n ⫽ 21; 19 mothers, 2 fathers) were in the prospective study. Children were between 2 and 18 years of age. Eleven children were male and 10 were female. The majority of children were either white (12; 57%) or black (7; 33%). The children were diagnosed with solid tumors (15; 72%); leukemias (3; 14%); and, other malignancies (3; 14%). All were interviewed within 7 days from the decision to participate in the phase I clinical trial.
Data Management and Analysis The investigators used qualitative, secondary analysis techniques to analyze the data (Hinds et al., 1997b; Santacroce, Deatrick, & Ledlie, 2000). Consistent with the FMS model, findings
were organized around parents’ views, management, and satisfaction with their participation. This article describes parents’ view of their participation with other results related to management (Angst, Deatrick, & Murphy-Moore, in progress) and spirituality (Murphy-Moore, Angst, & Deatrick, in progress), reported elsewhere. Access to the transcripts, demographic data, and Institutional Review Board (IRB) documents was successfully negotiated with Hinds and colleagues. IRB approval for this analysis was secured from the institution of the first author. No additional consent was needed from the parents because the original consent was sufficiently broad to accommodate the research questions for this study. Two of the investigators (JD, DA) read a complete set of the transcripts. First, themes in the data were identified in the transcripts of four subjects recorded in a case summary completed by each investigator. Second, through series of communications between the investigators, themes were consolidated and further defined. Third, the transcripts from the other 17 subjects were divided among the investigators for analysis and for preparation of case summaries and identified themes. The investigators also highlighted illustrative quotations in each transcript. Fourth, the investigators collaboratively prepared a summary of themes across all 21 cases, revising the themes as new insights developed. Fifth, support and understanding concerning each theme was sought in the literature. Criteria and procedures to strengthen the integrity of this analysis established by Hinds, Vogel, and Clarke-Steffen (1997b) and later described by Santacroce et al., (2000) were used in this analysis. A “pretest” using these criteria was completed with four transcripts by two of the investigators (JD, DA) to judge the quality of the data. The data set was judged favorably given: (1) the investigators had access to the research team and the data; (2) the data set was judged to be complete; (3) the data contained in the data set were of sufficient quality, completeness, and currency, and fit with the secondary research question; and (4) the primary research team was educationally and experientially expert.
Phase I Clinical Trials
Results Parents defined or viewed their situation in relation to their view of choice in the decision making, their expectations of the treatment, their interactions with health care providers, their children’s illness situation, and family considerations. Parental Themes Choices. All parents saw limited choices or no choice in the decision about whether to enter their children in a phase I clinical trial. Thirteen of the parents said that they did not have any choice in their situation. They knew that they signed a consent form, but, they didn’t think of it as a decision. There was no choice. . .It was just either this or we can’t treat you. I mean, it was definite. You either do this or there’s nothing we can do for you.
These parents described “choice” in terms of the promise of potentially “curative” treatment, not in terms of providing comfort or palliation. Eight parents acknowledged alternatives to trial participation, but did not feel that they had a choice. Because other treatments had already been exhausted, they could not deny participation in the trial if they wanted to continue “the fight.” As one parent remarked, There wasn’t really a choice in my mind because if I chose to not do anything then I would have been choosing to let her go and I’m not ready for that.
These parents described their situation as making a choice between participating in this clinical trial or doing “nothing.” Whether they thought a choice existed or not, parents described a range of reactions to the “decision,” from automatic to agonized, including one parent who stated, It’s like we’re going to do whatever we can to try and help her. . .I didn’t have to study on it or think about it hard. All I had to do was look at her and see how bad the pain she was in. They said there was a possibility this could help.
Expectations. Parents voiced a variety of expectations of the trial. These included providing treatment, buying time for another therapy, working a miracle, being altruistic, and delaying death.
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Most parents saw their child’s participation in the trial as a means of providing treatment to prolong life, through an uncertain treatment. Many parents had no idea if the treatment provided by the phase I agent would help or not, saying, “I don’t know which way we are going here.” Other parents began to question their decisions as they saw their children decline or saw little benefit from the trial agent. By trying this new drug, I’m still fighting the keep her here with me. . .I am beginning to know that may not happen.
One particular group of parents who wanted to prolong the lives of their children did so for a very specific reason. The phase I trial was a means to another end. That is, they were buying time for another therapy such as another clinical trial, tumor vaccine, or transplant: We had a child to store the cord blood and we are looking for a place now who can do cord blood transplants, which is one reason we are interested in the phase I treatment to put him into remission state, so that the cord blood transplant could be performed and possibly save our son’s life.
Some parents clearly emphasized the trial was a means to delaying their children’s death. Although related to the theme of “prolonging life,” this mother’s language about losing her daughter is certainly different: . . .If it did not [work], I want to say we tried. I keep thinking about losing her; it is the only thing I can think about.
Some parents were hoping for a cure or a miracle, whereas others stated that this was not their expectation. Many admitted that they wanted a miracle, but that they might not get one. Expectations about the efficacy of the proposed treatment were developed around many criteria, such as the occurrence of side effects, how others in the trial responded, and the mechanism of action and odds of success in relationship to the child’s previous treatments: This is my daughter’s second phase I study. The first one did not help; I know other children treated with this protocol that did well.
The desire to help other children with cancer in the future was evident in the altruistic expectations of some parents:
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We know the cancer he has is almost impossible to treat at this point and all we can do is hope for some miracle somewhere. Whether this works or not, we decided that it was just a chance. If nothing else, it will help somebody else down the road.
Another parent had a more complex altruistic motive that was mingled with the knowledge of family needs: . . .We feel that if he would die in a useful manner, it would kind of help cleanse us of the burden. . .give it a little bit of meaning. . .Whereas going home and dying on the bed to us is very meaningless and very frustrating, and just very damaging in every sense of the word. . .It’s family dealing with death in a very real [way]. . .At least we have made the effort. . .and enhanced some type of ongoing study. . .that would be my son’s legacy.
Interactions with health care providers. As families faced the option of phase I trial participation, health care providers provided information, concern, and alternatives. Parents discussed how physicians expressed concern about their children and helped them make the best decision. One parent stated: The thing that helped was the way he [the doctor] just had the confidence that this was a good drug for her. He let me know that it was still in study, but, he was very optimistic about it and he wanted to try it on her. I guess it was the way he presented it to me that was the deciding factor.
When health care providers demonstrated openness and presented options these were praised by parents. Parents clearly wanted information to help them problem solve. For instance, one provider explained which clinical trials could be tried first that would not limit options, that is, they had different eligibility criteria and could be sequenced to increased options. Some parents wanted more direction than others. They knew, however, that health care providers could not tell them whether they had made the “right” choice: What made it so hard for me is that I’m not a doctor, and he was so well-educated. He usually guides me well with decisions, but he couldn’t tell me what to do here, and it made me feel so helpless. . .I wanted so much to have someone else tell me that I had made the right decision, but there isn’t anyone who can tell me that.
Illness situation. The parents described their overall state of affairs in terms of their child’s
overall illness experience, the immediacy of the decision, and by efforts to keep trying. The children all had advanced cancer and had no aggressive treatment alternatives other than the phase I clinical trial. Parents knew that they had to make a decision quickly, otherwise death was imminent. Some parents said that they would bear tremendous guilt if they did not try the phase I trial. Others defined participation in the phase I trial as the only way to “keep trying” with a treatment that may or may not work. As one parent said, “You have to try everything. . .keep fighting to keep her here with me. You have to do what you have to do.” On some level, every one of the 21 parents continued to view their role as parent and their human need to keep trying: He [the doctor] didn’t give me that option [of stopping therapy]. I asked him if this was a last chance (crying) and he said he wouldn’t let it be.
Family considerations. Parental circumstances also played a role in how they viewed their children’s participation in phase I clinical trials, including practical issues, children’s capacity, and spirituality. Parents, in part, chose this treatment because of practical concerns including the location and the proximity of available treatment, ability to secure the treatment in the near future (time concerns), and issues that can be broadly defined as quality of life (e.g., amount of hospitalization, hair loss, vomiting). One family choose a particular phase I trial over another because the child could stay in an institution where he was comfortable. The parents commented that their son was characteristically not good at making change anyway, so changing institutions for an unknown treatment did not seem wise. For two families timing was an important issue in their decision. They could get into a trial right now in their present treatment facility and if that trial failed, they could go to the other institution as backup. Parents like this one also considered their children’s’ immediate needs and capacities: He was going to have to start a therapy and we want it to be the easiest thing for him, with the best results, which is a very fine line that you are walking.
The children’s capacity was described in terms of characteristics that bolstered parents’ decisions:
Phase I Clinical Trials She is a trooper. . . fighter. She does not give up. She was given 3-5 months to live, almost 2 years ago. She has a lot of faith. She kept telling me that she isn’t going to die.
Other parents variously described how their children’s physical condition, (e.g., good shape, weak) influenced their “decision.” Past or present child strength or resiliency influenced parents’ decision to choose trial participation. As one parent explained: We feel strongly that we are going to pursue any avenue at this point. . .as a matter of fact, probably the opposite of most parents who don’t want to see their kids suffer any more. We would rather see him go through a protocol with the hopes of getting some results than not. Because he is in very good shape. He is a pretty strong kid.
Spirituality was also central to many of the parents and is being described in another manuscript (Murphy-Moore, Angst, & Deatrick, in progress).
Discussion Study of phase III trials by Broome, et al. (2001b); Hall, Stevens, and Pletsch (2001); Liaschenko and Underwood (2001); Pletsch and Stevens (2001); and Snethen and Broome (2001) found that parents of children with cancer largely saw no “choice” in decisions around trial participation. Similarly, in this study of phase I trials, parents also saw little to no choice. Parents’ perceptions of “benefit” for these two groups were likely different, although their situations were similar; namely, an unfamiliar and devastating disease called childhood cancer. Benefit as traditionally defined would be more consistent with the situation of parents whose children are in phase III trials. Ethicists may ask philosophic questions, including concerns about the voluntariness (President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 1983) of parents’ decisions. Nelson and Rushton (2001) point out in their commentary of Broome’s study (2001a) that the subjects who blurred the line between research and treatment further emphasized the view that there was no choice but to pursue anything that is offered as a chance of survival. They further
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point out that a forced choice appears to diminish viable courses of action and to undercut the possibility of informed and voluntary consent. They conclude that those parents in Broome’s study (2001a) whose children were in need of a bone marrow transplant for treatment of cancer (phase III clinical trial) experienced a situation of limited choice but could give voluntary and informed assent/ permission in this situation. The American Society of Clinical Oncology (1997) states that participation of individuals with advanced cancer in phase I trials is ethically questionable to the extent that the “vulnerable” population does not know that they are going to die from their disease. They also cautioned that patients whose death is imminent might not be capable of analyzing risks of participation. When did the parents in this study consider that death was imminent? Parents stress a relational and collaborative, informed (child and health care provider) paradigm when making health care choices (Kirshbaum, 1996; Pike-Grimm, Degner, Small, & Mueller, 1999; Rushton, 1994). That is, they would like us to ask, what does it mean to you to be a good parent in this situation? Health care providers stress a decisional paradigm and would most likely ask in this situation, do you want to do this treatment for your child? When would parents say yes or no to this question (Kodish, Stocking, Ratain, Kohrman, & Siegler, 1992; Estlin, Cotterill, Pratt, Pearson, & Bernstein; 2000)? Whatever the answers to these questions, we know that parental, ethical, and clinical perspectives are different. Only further research will help ascertain how these diverse perspectives may or may not be complementary. Hinds and colleagues (1997a) found that the majority of the hardest decisions for parents whose children had died were those decisions around end-of-life care rather than those about “treatment.” The secondary analysis reported in this article did not put this decision into the context of the families’ overall view of end-oflife questions and issues. As a secondary analysis of parental cases in a study coded during the primary analysis to include parental themes regarding phase I clinical trials, 19 mothers and 2 fathers were included. The study was focused on their perceptions. The intent of the study was
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neither to describe the perceptions of the family as a whole, nor to ascertain their views about other members of the family who were not being interviewed. Future studies conceptualized and implemented as family research can prospectively gather data on these issues. For instance, Norton and Bowers (2001) recently identified helpful health care provider strategies in adult end-of-
life situations. They creatively enable the reader to understand strategies providers successfully used to help families shift their perspectives to the “big picture” regarding end-of-life and palliative care. Through such studies that systematically conceptualize the patients, families, and providers’ perspectives, we will better understand these situations, which are the heart and soul of nursing practice.
References Adamson, P.C., & Starr, S. E. (2001). Pediatric clinical trials: Design and performance. Research and Practice, 1(1), 41-47. American Society of Clinical Oncology. (1997). Critical role of Phase I clinical trials in cancer treatment. Journal of Clinical Oncology, 15(2), 853-859. Broome, M. E. (2001a). Response: A different type of classroom— on leading and learning. Journal of Family Nursing, 7(7), 214-218. Broome, M. E., Richards, D. J., & Hall, J. M. (2001b). Children in research: The experience of ill children and adolescents. Journal of Family Nursing, 7(1), 32-49. Denger, L. (1998). Preferences to participate in treatment decision-making: The adult model. Journal of Pediatric Oncology Nursing, 15(3), 3-9. Eisenhauer, E. A., O’Dwyer, P. J., Christian, M., & Humphrey. (2000). Phase I clinical trial design in cancer drug development. Journal of Clinical Oncology, 18(3), 684-692. Estlin, E. J., Cotterill, S., Pratt, C. B., Pearson, A. D. J., & Bernstein, M. (2000). Phase I trials in pediatric oncology: Perceptions of pediatricians from the United Kingdom Children’s Cancer Study Group and the Pediatric Oncology Group. Journal of Clinical Oncology, 18(9), 1900-1905. Hall, J. M., Stevens, P. E., & Pletsch, P. K. (2001). Team research using qualitative methods: Investigating children’s involvement in clinical research. Journal of Family Nursing, 7(1), 7-31. Hinds, P., Drew, D., DeSwart-Wallis, J., Gibson, F., Hollen, P., Hunt, J. et al. (1998a). Consensus statement: Decision making in pediatric oncology. Journal of Pediatric Oncology Nursing, 15(3, suppl 1), 24. Hinds, P., Oakes, L., & Furman, W. (2001a). End of life decision-making in pediatric oncology. In B. Ferrell & N. Coyle (Eds.). Oxford textbook of palliative care. New York: Oxford University Press. Hinds, P., Oakes, L., Furman, W., Foppiano, P., Olson, M. S., Quargnenti, A., et al. (1997a). Decision making by parents and healthcare professionals when considering continued care for pediatric patients with cancer. Oncology Nursing Forum, 24(9), 1523-1528. Hinds, P., Oakes, L., Furman, W., Quargnenti, A., Olson, M. S., Foppiano, P., & Srivastava, D. K. (2001b). End-of-life decision making by adolescents, parents, and healthcare providers in pediatric oncology. Cancer Nursing, 24(2), 122136. Hinds, P., Oakes, L., Quargnenti, A., Furman, W., Sandlund, J., Bowman, L., et al. (1998c). Treatment decision
making for pediatric oncology patients by their parents and healthcare professionals. Funded by the Association of Critical Care Nurses. Hinds, P., Oakes, L., Quargnenti, A., Furman, W., Sandlund, J. T., Bowman, L., et al. (1998b). Challenges and issues in conducting descriptive decision-making in pediatric oncology: A tale of two studies. Journal of Pediatric Oncology Nursing, 15(3, suppl 1), 10-17. Hinds, P., Votel, R., & Clarke-Steffen, L. (1997b). The possibilities and pitfalls of doing a secondary analysis of a qualitative data set. Qualitative Health Research, 7(3), 408-424. Kirschbaum, M. (1996) Life support decisions for children: What do parents value? Advances in Nursing Science, 19(1), 51-71. Knafl, K., & Deatrick, J. (1990). Family management style: Concept analysis and development. Journal of Pediatric Nursing, 5(1), 209-214. Kodish, E., Stocking, C., Ratain, M. J., Kohrman, A., & Siegler, M. (1992). Ethical issues in phase I oncology research: A comparison of investigators and institutional review board chairpersons. Journal of Clinical Oncology, 10(11), 1810-1816. Liaschenko, J. & Underwood, S. M. (2001). Children in research: Fathers in cancer research—meanings and reasons for participation. Journal of Family Nursing, 7(1), 71-91. Nelson, R. M., & Rushton, C. H. (2001). Commentary on special issue on informed consent with families of ill children: Understanding devastation and difference in informed permission and assent. Journal of Family Nursing, 7(1), 208213. Norton, S., & Bowers, B. (2001). Working toward a consensus: Providers’ strategies to shift patients from curative to palliative treatment choices. Research in Nursing & Health, 24, 258-269. Pierce, P., & Hicks, F. (2001). Patient decision-making behavior: An emerging paradigm for nursing science. Nursing Research, 50(5), 267-274. Pike-Grimm, K., Degner, L., Small, A., & Mueller, B. (1999). Preferences for participation in treatment decisionmaking and information needs of parents of children with cancer: A pilot study. Journal of Pediatric Oncology Nursing, 16(1), 13-24. Pletsch, P. M., & Stevens, P. E. (2001). Children in research: Informed consent and critical factors affecting mothers. Journal of Family Nursing, 7(1), 50-70. President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research.
Phase I Clinical Trials (1983). Deciding to forego life-sustaining treatment. Washington, DC: U.S. Government Printing Office. Rushton, C. (1994). Ethical decision-making: The role of parents. Capsules and Comments in Pediatric Nursing, 1(2), 1-10. Santacroce, S., Deatrick, J., & Ledlie, S. (May/June 2000). Secondary analysis of qualitative data: A means of collaboration in HIV-related research. Journal of the Association of Nurses in AIDS Care, 11(3), 99-104. Smith, M., Bernstein, M., Bleyer, W., Borsi, J., Ho, P.,
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Lewis, I., et al. (1998). Conduct of phase I trials in children with cancer. Journal of Clinical Oncology, 16(3), 966-978. Snethen, J. A., & Broome, M. E. (2001). Children in research: The experiences of siblings in research is a family affair. Journal of Family Nursing, 7(1), 92-110. Wiley, F., Ruccione, K., Moore, I., McGuire-Cullen, P., Fergusson, J., Waskerwitz, M., et al. (1999). Parents’ perceptions of randomized pediatric clinical trials. Cancer Practice, 7(5), 248-256.