High-quality informed consent is critically important to pediatric phase I cancer research. Of significance, only 32% of parents demonstrated substantial understanding of the scientific purpose of phase I research, which is consistent with studies that assessed understanding in adult phase I research participants.7,26,27
Notably, 35% of parents demonstrated virtually no understanding. Further examination of physician-parent communication revealed inadequate discussion of crucial topics inherent to phase I research. Despite deficiencies in physician explanation of key concepts necessary for truly informed consent9
and deficiencies in parental understanding, 95% of parents enrolled their child onto the phase I trial offered.
Physician explanation of drug safety (DLT), dose finding (MTD), and dose escalation did not ensure parental understanding. Thus, persistent therapeutic misconceptions13
may limit parents' understanding of the scientific purpose and nature of the study. Future research should examine the degree to which patients and parents understand the risks and benefits of phase I research, alternatives to participation, and factors associated with therapeutic misconceptions, and whether parents understand that phase I trials are rarely curative and may impose significant patient burden.
Importantly, physician explanation of dose cohorts and explanation of the goals of the applicable phase I protocol were associated with greater parental understanding, pointing to ways in which physicians can improve the informed consent process and communication in phase I research. Several adult oncology studies have demonstrated the value of training physicians in such methods.28–30
Our own research demonstrates that physician training in the pediatric oncology setting increases the use of rapport-building statements31
and open-ended methods of eliciting questions in ICCs.32
Future research should consider ways in which these interventions can be modified and efficiently delivered in the phase I context. Physicians should be trained in strategies and techniques for more effectively explaining the scientific purpose of phase I research and related concepts, such as dose cohorts.
Because the mean age of patients in this sample was only 11 years, it is remarkable that the child attended 83 of 85 ICCs observed. This finding may reflect a significant cultural transformation in the way we talk to children about the life-threatening nature of their cancer. Research has demonstrated a growing consensus among parents33
and health care providers34,35
supporting honest discussion with children. Future examination of young patients' perspectives on clinical research and the informed consent process may help guide researchers and regulators in developing ICC processes that ensure the appropriate involvement of children. Parents' views about the informed consent process have also yielded informative insights for improving the process and developing interventions.36–40
It is essential that this line of work continues to ensure that those who matter most—child research participants and their families—are heard and their concerns are addressed.
Several barriers to high-quality informed consent remain. In our study, lower SES and racial/ethnic minority status were associated with poorer parental understanding, although physician explanations did not differ in those groups. Findings emphasize the need for targeted interventions to improve the informed consent process for families of lower SES or of racial/ethnic minority status. The use of culturally sensitive support materials developed in collaboration with patients and families may facilitate understanding for these groups.41
Our findings also suggest that the ICC is not the sole determinant of parental understanding. In 23 of 60 cases, parental understanding exceeded physician explanation. Therefore, parents clearly learn about research from other sources (eg, referring physician, Internet, other parents, consent form). Future research should seek to make optimal use of these additional information sources. For example, a parent with previous personal experience may serve as a supportive source of information for other parents considering enrollment, offering a first-hand explanation of the phase I trial that parents can easily understand. Anticipatory guidance, such as showing parents a DVD before the ICC,42
may also improve informed consent for phase I trials.
These results must be interpreted in light of study limitations. Although participants were recruited from six of the most active pediatric phase I research programs, these may not be representative of other programs. Because of the sample size, we only had statistical power to detect large effect sizes; however, 85 participating families is a fairly substantial sample considering that 130 to 200 patients are enrolled annually onto Children's Oncology Group phase I studies. Despite our attempt to observe and record the ICC process in its entirety, it is also possible that physicians and parents had unobserved discussions about the trial. Additionally, conversations regarding alternative options such as palliative care or hospice, as well as conversations introducing families to phase I trials, may have already taken place before the ICC. A lack of data regarding additional sources limits our understanding of information obtained outside of the ICC. Strengths of the study include direct observation of informed consent paired with follow-up parent interview, rigorous measurement of parental understanding, and a novel methodologic approach to comparing disclosure and understanding (). This work provides a comprehensive analysis of these important conversations and the impact of communication on parental understanding.
In sum, children with refractory cancer who are recruited for phase I trials represent one of the most vulnerable populations of human study participants. Although findings show that the children are almost always present at the ICC, substantial barriers and ethical challenges to high-quality informed consent remain. This study adds a new conceptual framework regarding the ethics of phase I cancer research that is relevant to both adults and children with terminal cancer. Results highlight the need for future examination of the role of children in phase I ICCs; of parent and patient understanding of risks, benefits, and alternatives to participation; and of interventions that can improve physician-parent communication and informed consent.