Phase 1 trials are critical for the development of new anticancer therapies. The traditional goal of phase 1 trials is to determine maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of a new agent and establish an appropriate dose for use in subsequent phase 2 trials. 1 Phase 1 trials are considered for children with refractory tumors when conventional therapies have proven ineffective and cure is unlikely. There will always need to be a “first time” a drug is used in humans, and waiting until the new agent has been exhaustively studied in adults will slow progress against childhood cancer. Ensuring early pediatric access to such therapies will require a fuller understanding of the balance between protection from risk and the potential for benefit. Along with the need to gather pediatric-specific data to inform the rational use of each new agent comes an equally compelling responsibility to obtain meaningful informed consent (IC).
IC is the process by which decision making about phase 1 trial participation takes place. In pediatrics, IC is composed of parental permission and assent of older children. 2 Communication and decision-making in the phase 1 context are fraught with difficulties for both physicians and patients. Some are concerned that the severity of the disease and poor prognosis inherent in the phase 1 context can increase the vulnerability of patients and their families, confounding the already difficult task of obtaining truly IC.3, 4 Families are confronted with difficult decisions in weighing the risks and benefits of participating in phase 1 trials while considering other options, including hospice/palliative care programs.5 Physicians often report a tension between providing a truthful prognosis and presenting experimental drug options while still maintaining hope for the family.6-9 They may also experience role conflict between obligations to advance medical science for the benefit of future patients and the best interests and needs of the child who is a potential research subject.10 Furthermore, given the sparse data regarding how decision-making transpires during these stressful times, physicians are left with little guidance. These concerns demonstrate the need for research regarding the communication that takes place around decisions regarding pediatric phase 1 cancer studies.10
In this study, we present data about the experience and opinions of pediatric oncologists with the IC process (ICP) for phase 1 childhood cancer trials. The goal of the study is to better understand the ICP from the perspective of those who are expected to communicate in this challenging context. We set out to discover perceived goals of and obstacles to good IC, and to identify physician beliefs regarding parental comprehension of various aspects of phase 1 trials. Finally, we hoped to learn what suggestions doctors might have to improve the ICP.
MATERIALS AND METHODS
- Top of page
- MATERIALS AND METHODS
- CONFLICT OF INTEREST DISCLOSURES
Results discussed in this study are a component of a larger ongoing multisite study, the Phase I (One) Informed Consent (POIC) project, designed to understand communication between physicians and families, as well as comprehension, and decision-making of parents and older pediatric patients. The 6 pediatric cancer phase 1 centers participating include St. Jude Children's Research Hospital, Memphis, Tennessee; Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Children's Hospital Pittsburgh, Pittsburgh, Pennsylvania; National Cancer Institute-Pediatric Oncology Branch, Bethesda, Maryland; Children's National Medical Center, Washington, DC; and Children's Hospital and Regional Medical Center, Seattle, Washington. This study was approved by Institutional Review Boards at each data collection site and at Cleveland Clinic, Cleveland, Ohio (administrative home). Site coinvestigators, along with research associates, identified attending physicians and fellows who would potentially conduct phase 1 IC conferences at their individual sites. Once the 146 physicians were identified, the study was introduced to these pediatric oncologists and the instrument was administered. Data collection began in February 2008 and ended in December 2008.
The instrument was originally developed for a pilot study surveying both physicians and parents involved in IC for pediatric cancer clinical trials. 11 It was subsequently modified for use in a larger study designed to understand the ICP for phase 3 leukemia trials at 5 major institutions across the United States.12 The current instrument was then modified for use in the context of IC for phase 1 pediatric cancer trials. It is comprised of 25 items and is available on request from the corresponding author. Although this specific questionnaire was not pilot tested within the phase 1 context, we believe it to be a valid and reliable instrument based on our previous experiences with the original instrument as stated above.
Quantitative responses were analyzed using SPSS statistical software (version 14.0; SPSS Inc, Chicago, Ill). We computed aggregate data for all variables based on the total sample of 103 responses. Categorical associations between physician gender and type of IC training and other categorical variables within the questionnaire were assessed by means of chi-square statistics. Significant associations among continuous variables were tested by means of Pearson correlations. Linear regression analysis was also performed on selected outcomes to identify major independent predictors for each.
Physicians were asked an open-ended question, “How do you think we can make the Phase 1 informed consent process better?” Responses were transcribed and then independently categorized into 8 themes by 2 of the article's authors (T.Y. and A.Y.) using semantic content analysis. 13, 14 Categorized data were ranked according to frequency of suggestions in each category.
- Top of page
- MATERIALS AND METHODS
- CONFLICT OF INTEREST DISCLOSURES
One key to understanding and ultimately improving the quality of IC is to better understand the views of physicians at the nexus of investigational medicine and clinical care. This study provides data to enrich that understanding. We found that pediatric oncologists tend to present phase 1 trials as an option rather than a strong recommendation and feel reluctant to influence decisions of families about these studies. They may share therapeutic optimism with patients and families but are also realistic about the prospect of medical benefit. They believe most but not all parents understand key concepts involved in consent to this type of research, and had ample suggestions for how to improve the ICP.
Estlin et al conducted a study to determine perceptions of pediatricians on phase 1 trials more than a decade ago. 15 They surveyed 53 physicians from the United Kingdom Children's Cancer Study Group (UKCCSG) and 78 from the former Pediatric Oncology Group (POG). In contrast to our specific focus on IC, the study by Estlin et al covered a range of ethical topics including physicians' perspectives of the challenges associated with phase 1 trials, perceived reasons for enrolling a child onto phase 1 trials, and opinions about benefits and risks of participating in these trials. They then contrasted and compared the responses of American and British physicians. Similar to our findings, most physicians in the study by Estlin et al believed that patients receive some form of medical benefit from participating in phase 1 trials.15 Results presented here complement this previous research.
Physicians viewed the goal of providing information to families as the highest priority for the phase 1 ICP. In our study, pediatric oncologists did not appear to encourage or strongly recommend these trials, but rather it appears that they tend to emphasize a more neutral framework. Approaches described as “no attempt to influence their decision” and “suggesting that other (bold in original instrument) children will benefit” were endorsed by 93 of 99 respondents. They considered the 2 most formidable obstacles to good IC to be 1) parents' eagerness to try any treatment after a recurrence/refractory diagnosis for their child; and 2) maintaining hope for the parents/patient while providing accurate, honest information regarding the child's condition. Previous studies have indicated that patients often enroll in phase 1 trials at least partially because of hope for cure. 15-17 In this way, our findings are compatible with previous results in both adult and pediatric contexts.
Male physicians were significantly more likely to endorse the “no attempt to influence” approach, whereas female physicians were more likely to suggest to parents that other children will benefit from what is learned in phase 1 studies.
A substantial body of work in feminist ethics suggests emphasis on relationships and responsibility can help to reframe the more traditional understanding of morality. 18, 19 The fact that female physicians approach the ICP in a manner more connected to this way of thinking supports further conceptual and empirical investigation. Pure neutrality may not be the right approach to pediatric phase 1 consent, and benefits that may accrue to other children is certainly worthy of attention.
Assent is another very challenging component of the ICP. In our previous research, physicians reported mean ages of 11 years and 13 years as the youngest ages child patients should be included in a discussion of IC and involved in decision-making about participation in phase 3 oncology trials, respectively. 11 Physicians from the current study reported the mean youngest age for a child to be included in a discussion of IC and involved in decision making about participation in phase 1 trials as 10 years and 12 years, respectively. One potential reason for this difference in ages is the nature of phase 1 trials when compared with phase 3 trials. Often, children who are approached to participate in phase 1 trials have experienced prior therapy and/or have participated in phase 2 or 3 research and may indeed have a better understanding of the concept of clinical studies. Physicians' knowledge that a phase 1 trial is unlikely to result in direct medical benefit to participants, but rather aid in scientific advancement for pediatric cancer more generally, may also factor into a decision to include child patients in discussions and decisions about phase 1 trials at younger ages. Interviews with older children and teenager participants in the ICP, which highlight their opinions and preferences, could provide a critical perspective in future research.
The issue of therapeutic misconception in phase 1 trials continues to spark ethical debate. Although 60% of surveyed physicians believe patients receive therapeutic/medical benefit from trial participation, 15% among this group annotated on the survey's margins that only a small percentage of patients do actually benefit from phase 1 studies. Results from this item indicate that physicians are realistic about potential therapeutic benefits of phase 1 trials but at the same time reveal therapeutic optimism 20 and hope for patients who are phase 1 candidates.
Limitations of the current study include the fact that the sample was drawn from only 6 of 20 centers in the Children's Oncology Group Developmental Therapeutics Consortium conducting phase 1 trials, and lack of real-time information regarding the ICP. The results reported here may not generalize to smaller centers with less experience. Ongoing research based in direct observation and recording of phase 1 ICPs followed by interviews with patients and parents and case-specific responses from physicians will help to fill the gap.
Future research should examine perspectives of older child patients considering phase 1 trials. Detailed qualitative research focused on interactions between physicians, parents, and patients may offer more specific suggestions to help improve this process. Educational efforts around this topic that include both physicians and families are essential to improving IC in phase 1 pediatric cancer trials for all stakeholders—physicians, parents, and child patients.