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.

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.

Staged informed consent for a randomized clinical trial in childhood leukemia: impact on the consent process.

BACKGROUND: Children Cancer Group (CCG) 1991 is the first childhood acute lymphoblastic leukemia trial within CCG that allowed the utilization of a staged approach to the consent process. METHODS: One hundred and forty subjects participated in the Project on Informed Consent which compared the primary outcome measures in the consent process of patients enrolled in CCG-1991 with those enrolled in other CCG leukemia studies. RESULTS: The parents' trust scores were higher for the CCG-1991 compared with other protocols. Eighty percent of parents enrolled in CCG-1991 understood the distinction between the randomized clinical trial and the standard treatment arm, compared with 62.5% in the other studies, P = 0.05. Multiple other outcome measures suggested a positive impact from staged informed consent. CONCLUSIONS: Our results suggest that a consent process with a staged approach can help investigators obtain a more truly informed consent. Future research is needed to confirm the benefits of the staged approach to the informed consent process.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The need for anonymous genetic counseling and testing.

Concerns are mounting about the risks of genetic discrimination resulting from the release of predictive and presymptomatic genetic test results to employers, insurers, and others. The ability to keep this information confidential is questionable, particularly in view of the expansion of electronic medical databases. One solution is to afford individuals access to anonymous genetic counseling and testing. Probands would be identified only by a code that would not reveal personal information, and test results would be stored, retrieved, and released solely on the basis of this code. The experience with anonymous HIV testing, while not completely analogous, suggests that such an approach would be both practical and effective.