The relationship between eligibility criteria and adverse events in randomized controlled trials of hematologic malignancies.

To minimize adverse events (AEs) unrelated to drugs and maximize the likelihood of drug approvals, eligibility criteria for randomized controlled trials (RCTs) may be overly restrictive. The purpose of this study was to determine if RCTs in hematologic malignancies exclude patients irrespective of known toxicities or observed AEs. MEDLINE was searched from 1/2010 to 1/2015 for RCTs published in high-impact journals. Of 97 trials, 33% were conducted in leukemia, 28% in lymphoma, 34% in multiple myeloma and 5% in myelodysplastic syndromes or myelofibrosis. Expected toxicities at thresholds of ⩾10%, ⩾5% and <5% were not correlated with cardiac, hepatic or renal eligibility criteria (logistic regression). To explore this lack of correlation we tested the concordance of expected toxicities and eligibility criteria using a modified version of McNemar's test: at each threshold, hepatic, renal and cardiac expected toxicities were significantly discordant with eligibility criteria. Hepatic and renal eligibility criteria were also not correlated with observed AEs, P=0.69 and P=0.77, respectively, but a significant correlation was detected between cardiac eligibility criteria and observed AEs, P=0.02. Thus, the analyzed RCTs excluding patients with organ dysfunction do not reflect expected toxicities, based on prescription drug labels/prior experience, or reported AEs on the trials.

Ethical issues in phase I oncology research: a comparison of investigators and institutional review board chairpersons.

PURPOSE: Phase I research trials assess the safety of agents never before administered to humans. In the field of oncology, this practice raises several important ethical questions. We examined the ethics of these trials by surveying phase I oncology investigators and institutional review board (IRB) chairpersons at major cancer research centers around the country. METHODS: Questionnaires were mailed to 78 investigators and 47 chairpersons to obtain their views on the ethical propriety of conducting phase I oncology research, and on institutional practice regarding these trials. The response rate was 68% in each group. RESULTS: The majority of each group reported that phase I oncology trials face no more scrutiny or resistance in their institution's IRB process than other research protocols. Nevertheless, IRB chairpersons were more likely than investigators to favor special procedural safeguards to protect subjects in phase I oncology trials. Nearly all respondents agreed that although actual medical benefit was very uncommon, most patients entered for a chance at a therapeutic effect. Investigators were more likely than chairpersons to report that patients obtained psychologic benefit from participation in phase I trials. CONCLUSION: Although individual IRB chairpersons and oncology investigators may have important differences of opinion concerning the ethics of phase I trials, these disagreements do not represent a widespread area of ethical conflict in clinical research.

Perceptions of cancer patients and their physicians involved in phase I trials.

PURPOSE: In an attempt to understand some of the complex issues related to the participation of cancer patients in phase I trials, and the perceptions of patients toward these trials, we conducted a pilot survey study of 30 cancer patients who had given informed consent to participate in a phase I trial at our institution. Concurrently, the oncologists identified by the surveyed patients as responsible for their care were surveyed as well. PATIENTS AND METHODS: Twenty-seven of 30 consecutive patients agreed to and completed the survey. Patients were surveyed before they received any investigational agents. Eighteen oncologists participated in this survey study. RESULTS: Eighty-five percent of patients decided to participate in a phase I trial for reasons of possible therapeutic benefit, 11% because of advice/trust of physicians, and 4% because of family pressures. Ninety-three percent said that they understood all (33%) or most (60%) of the information provided about the trials in which they had decided to participate. Only 33% were able to state the purpose of the trial in which they were participating, with patients able to state the purpose of phase I trials being more educated (P = .01). Surveyed oncologists had wide-ranging beliefs regarding expectations of possible benefits and toxicities for their patients participating in phase I trials. CONCLUSION: Cancer patients who participate in phase I trials are strongly motivated by the hope of therapeutic benefit. Altruistic feelings appear to have a limited and inconsequential role in motivating patients to participate in these trials. Cancer patients who participate in phase I trials appear to have an adequate self-perceived knowledge of the risks of investigational agents. However, only a minority of patients appear to have an adequate understanding of the purpose of phase I trials as dose-escalation/dose-determination studies.

Genetic testing for renal diseases: medical and ethical considerations.

Advances in understanding the genetic basis of renal disorders will soon allow for the clinical use of genetic diagnostic testing. In this article, we review renal diseases with a known genetic basis and the current methods available for genetic testing. We then examine the potential medical indications for genetic testing, with special attention to autosomal dominant polycystic kidney disease (ADPKD). Because clinicians will be faced with patients considering genetic testing, we review the ethical considerations regarding genetic testing for renal diseases, recent genetic privacy legislation, and the special role genetic testing may have in transplantation. We conclude with a review of the necessary elements of informed consent, which provides the ethical foundation for patients deciding about genetic testing with the assistance of their physicians.

Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions.

Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers regarding the risks and benefits of transplantation. A survey of 100 patients and their health care providers was undertaken. Assessment of risk was by a reference gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not accepting risk, as well as assessment of agreement on risks recommended by health care providers and accepted by patients. Sixty-three of 100 patients were willing to accept some short-term risk of mortality in exchange for the certainty of cure. Fifteen patients were willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were identified between those accepting risk and those not accepting risk. There was no agreement between the recommendations of health care providers and the risk accepted by patients. A substantial proportion of adults with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision to accept risk is influenced by individual patient values that cannot be easily quantified and that do not correlate with the assessment of the health care provider. Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell transplantation in sickle cell patients should be encouraged.

Commentary: risks and benefits, testing and screening, cancer, genes and dollars.

Author argues that the current, restrictive policy for genetic screening for cancer risk is appropriate but that diagnostic testing decisions should not be so narrowly regulated.

The return of research results to participants: pilot questionnaire of adolescents and parents of children with cancer.

PURPOSE: The offer to return research results to participants is increasingly recognized as an ethical obligation, although few researchers routinely return results. We examined the needs and attitudes of parents of children with cancer and of adolescents with cancer to the return of research results. METHODS: Seven experts in research ethics scored content validity on parent and adolescent questionnaires previously developed through focus group and phone interviews. The questionnaires were revised and provided to 30 parents and 10 adolescents in a tertiary care oncology setting. RESULTS: The content validity index for individual questions and the overall questionnaires scored as 0.86 for both questionnaires. All 30 parents and 10 adolescents who agreed to participate returned questionnaires. The majority (>95%) indicated that they had a strong or very strong right to receive results. Letter or e-mail was a satisfactory means to return results described as good or neutral (66% parents, 100% adolescents) but more participants wished face-to-face disclosure of results with negative implications (50% parents, 60% adolescents). Very few wanted results disseminated through a Web site. The majority acknowledged the need for peer-review before disclosure (60% of adolescents and parents) but did not want "to be the last to know." CONCLUSIONS: Our data suggest that pediatric oncology patients and parents of children with cancer strongly feel that they have a right to research results, and that they wish to receive these in a timely manner.

Ethical issues in emerging new treatments such as growth hormone therapy for children with Down syndrome and Prader-Willi syndrome.

As new therapies and new applications of existing drugs expand, pediatricians are often in the position of trying to decide when and whether use of a new treatment is appropriate. In this paper, we address this dilemma by focusing on ethical issues in the use of growth hormone therapy for children with Down syndrome and Prader-Willi syndrome as an example. We discuss six major questions that link scientific and ethical considerations in analyzing these difficult issues.

Continuous propofol infusion for the relief of treatment-resistant discomfort in a terminally ill pediatric patient with cancer.

PURPOSE: To determine the effectiveness of propofol as adjunctive therapy in the treatment of drug-resistant discomfort in a terminally ill pediatric patient. PATIENT AND METHODS: A 3-year-old child with advanced rhabdomyosarcoma and severe drug-resistant discomfort was studied. Propofol was administered as adjunctive therapy to provide relief from severe discomfort. RESULTS: Propofol was initiated with a loading dose of 1.2 mg/kg followed by a continuous intravenous infusion of 1.2 mg/kg/h. Over the next 10 days, additional loading doses were administered and the infusion rate was increased to a maximum of 32 mg/kg/h. After the addition of propofol, our patient's discomfort improved greatly without the occurrence of propofol-associated adverse events. CONCLUSIONS: Propofol appears to be an effective adjunct to opioids and a promising alternative to barbiturate therapy in the treatment of drug-resistant discomfort in terminally ill pediatric patients.

Diagnosis, disclosure, and informed consent: learning from parents of children with cancer.

PURPOSE: The aim of this study was to learn about and to describe retrospective perceptions of parents of the circumstances of their child's cancer diagnosis and of the informed consent process. METHODS: Professional moderators conducted three focus groups with 22 parents of children with cancer who were eligible for enrollment in a Children's Cancer Group clinical trial research protocol. Each focus group consisted of seven to nine parents and was audiotaped and transcribed. RESULTS: Parents' descriptions of the early phase of their child's illness yielded the following themes: dialogues regarding the diagnosis and treatment options occurred amidst tremendous stress; a sense of constraint and lack of control were common; parents experienced variable degrees of choice regarding their child's participation in a clinical trial; and parents provided suggestions about how to improve the informed consent process. Overall, parents did not verbalize distinctions between their understanding of their child's medical treatment, research participation, and other aspects of their child's cancer experience. CONCLUSIONS: Based on these results, the authors conclude with practical recommendations for health care professionals caring for children with cancer and call for future research about parents' understanding of treatment options, the nature of clinical trials, and experience with the diagnostic and early treatment phase of childhood cancer with larger samples of parents from multiple sites.

Informed consent for pediatric leukemia research: clinician perspectives.

BACKGROUND: Good, fully informed consent is critical to the ethical conduct of clinical cancer research. The authors examined clinician perspectives on informed consent for pediatric research by surveying clinicians at five major medical centers that routinely enroll patients in Children's Cancer Group studies. METHODS: Building on a pilot study, a questionnaire was designed to elicit clinicians' general opinions, approaches, and suggestions related to informed consent in pediatric leukemia trials. Questionnaires were mailed to 132 clinicians. Eighty-nine questionnaires were returned, along with 13 nonparticipant forms notifying us of the clinician's inability to participate because of a lack of experience in pediatric informed consent. The response rate was 75%. RESULTS: Providing information so that families can decide about study entry was ranked as the most important goal of the informed consent process, whereas parents' state of shock was rated the most significant obstacle to good informed consent. Clinicians cited high levels of parental comprehension of key aspects of clinical research studies and reported information overload and increased anxiety as effects of the informed consent process on parents. Several key items were associated with clinicians' gender, race, and professional experience. Finally, one open-ended question yielded 126 suggestions for how to improve the informed consent process that were grouped into 10 meaningful categories. CONCLUSIONS: Clinicians report a range of approaches, opinions, concerns, and suggestions for improving the informed consent process. The article proposes that their views and suggestions be integrated with those of parents and patients in attempts to survey and improve informed consent in pediatric oncology.

Activated protein C resistance in a neonate with venous thrombosis.

A term infant had a life-threatening inferior venal caval thrombosis during the first 24 hours of life. The plasma from the infant and his mother was found to be resistant to activated protein C and to be heterozygous for the factor V mutation (FV Leiden) associated with this disorder. The presence of this hereditary disorder should be considered in infants with thrombosis and in infants with conditions predisposing them to thrombosis.

Bone marrow transplantation for sickle cell disease. A study of parents' decisions.

BACKGROUND: Bone marrow transplantation has been shown to cure sickle cell disease, but it carries a 15 percent mortality risk. To determine whether parents would accept this risk to cure their children of sickle cell disease, we interviewed parents of children with sickle cell disease who were being followed in a university hospital clinic. METHODS: We assessed parents' attitudes by using questions based on the standard reference-gamble paradigm. After we gave them descriptions of bone marrow transplantation and graft-versus-host disease (GVHD), the parents were presented with a series of hypothetical situations. In the first situation, bone marrow transplantation was described as offering certain (100 percent) survival with cure of sickle cell disease. In subsequent descriptions, the mortality rate associated with bone marrow transplantation was increased by 5 percent increments. The parents indicated the highest mortality risk at which they would consent to the procedure in order to cure their children. RESULTS: In order to obtain a cure for their children, 36 of 67 parents (54 percent) were willing to accept some risk of short-term mortality, 25 of 67 (37 percent) were willing to accept at least the 15 percent short-term mortality risk we estimate to be the current figure for bone marrow transplantation, and 8 of 67 (12 percent) were willing to accept a short-term mortality risk of 50 percent or more. Nine parents (13 percent) said they would accept both a mortality risk of 15 percent or more and an additional 15 percent risk of GVHD. The parents' decisions were not related to the clinical severity of their children's illness. CONCLUSIONS: At current rates of mortality and morbidity with bone marrow transplantation, a substantial minority of the parents of children with sickle cell disease may consent to bone marrow transplantation for their children. Parental attitudes should be factored into decisions about whether to offer bone marrow transplantation to children with sickle cell disease.

Ethical issues in umbilical cord blood banking. Working Group on Ethical Issues in Umbilical Cord Blood Banking.

OBJECTIVE: Banking umbilical cord blood (UCB) to be used as a source of stem cells for transplantation is associated with a set of ethical issues. An examination of these issues is needed to inform public policy and to raise the awareness of prospective parents, clinicians, and investigators. PARTICIPANTS: Individuals with expertise in anthropology, blood banking, bone marrow transplantation, ethics, law, obstetrics, pediatrics, and the social sciences were invited to join the Working Group on Ethical Issues in Umbilical Cord Blood Banking. EVIDENCE: Members were assigned topics to present to the Working Group. Following independent reviews, background materials were sent to the Working Group. CONSENSUS PROCESS: Individual presentations of topics at a 2-day meeting were followed by extensive group discussions in which consensus emerged. A writing committee then drafted a document that was circulated to the entire Working Group. After 3 rounds of comments over several months, all but 1 member of the Working Group agreed with the presentation of our conclusions. CONCLUSIONS: (1) Umbilical cord blood technology is promising although it has several investigational aspects; (2) during this investigational phase, secure linkage should be maintained of stored UCB to the identity of the donor; (3) UCB banking for autologous use is associated with even greater uncertainty than banking for allogeneic use; (4) marketing practices for UCB banking in the private sector need close attention; (5) more data are needed to ensure that recruitment for banking and use of UCB are equitable; and (6) the process of obtaining informed consent for collection of UCB should begin before labor and delivery.

Informed consent in the Childrens Cancer Group: results of preliminary research.

BACKGROUND: Informed consent is critical to the ethical conduct of pediatric cancer clinical research. Research regarding such consent has been limited. METHODS: After conducting a background survey of institutional practice from principal investigators (PIs) at 113 Childrens Cancer Group (CCG) centers, the authors obtained more detailed data regarding informed consent from 23 parents of children recently enrolled in CCG research trials and from 23 clinician-investigators at 5 CCG institutions. RESULTS: Approximately 73% of PIs responded to the background survey, providing context in which to interpret the more detailed information. Parents reported that they found the informed consent process helpful, although somewhat confusing. Satisfaction with informed consent was not related to ethnicity or education level. Parents found discussion with staff more helpful than the consent document, and the majority reported that the amount of information conveyed was appropriate. Although only 3 parents (13%) reported that too much information was given, nearly 50% of the investigators believed too much information usually is provided. All investigators believed that patients benefit from participation in CCG studies; the majority recommend that the child be enrolled on study, and the majority believe the major obstacle to good informed consent is parents' "state of shock." CONCLUSIONS: Parents expressed general satisfaction with the consent process. By contrast, clinician responses indicate dissatisfaction with the informed consent process. Future research must include more centers and larger numbers of parents of children who we enrolled as well as those who declined to participate in CCG studies, examine consent in minority subgroups, and further investigate the role of clinician-investigators and their interaction with parents and children during the informed consent process.