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Keywords:

  • informed consent;
  • pediatric oncology;
  • phase 1 trials;
  • ethics;
  • physicians' perspectives

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

BACKGROUND.

This study was conducted to gather pediatric oncologists' opinions about and suggestions for improvement of informed consent (IC) in pediatric phase 1 cancer trials.

METHODS.

A questionnaire designed to elicit perspectives was distributed to 146 physicians at 6 participating institutions. A total of 103 completed surveys were returned for a 71% response rate.

RESULTS.

Pediatric oncologists believe providing information so families can decide about phase 1 study entry is the most important goal of the IC process (ICP). The majority of physicians (64%) report that they describe the phase 1 study without any attempt to influence parents' decisions. Several answers provided by physicians were associated with their gender and prior IC training. 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. Responses to an open-ended question provided 63 suggestions for improvement of the ICP, including document and training changes and tools to enhance physician-family communication.

CONCLUSIONS.

Pediatric oncologists tended to present phase 1 trials as an option rather than a strong recommendation and were reluctant to influence decisions of families about these studies. 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. Future research and education efforts around this ethically challenging topic were warranted. Cancer 2010. © 2010 American Cancer Society.

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

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

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.

Statistical Analysis

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.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Demographic Data

A total of 103 completed surveys were returned for a response rate of 71%. Approximately 81% of study participants were attending physicians, and 19% were fellows in training (Table 1). The majority of participants were white, and there was an equal distribution of male and female physicians. When asked the question “How did you learn to discuss IC in pediatric cancer research?”, the instrument provided 2 options: 1) through a formal training program and 2) through informal training by observing mentors with instructions to check all that apply. Most physicians (79%) who completed our survey selected informal training only.

Table 1. Physician Characteristics (N=103)
CharacteristicValue
  • SD indicates standard deviation.

  • a

    For our purposes, an Attending is defined as a physician having completed residency and fellowship in pediatric oncology, whereas a Fellow is defined as a physician currently in training for, but has yet to complete, a fellowship in pediatric oncology.

Mean physician age (SD), y42 (9.5)
Gender 
 Male51 (49.5%)
 Female52 (50.5%)
Race 
 White83 (83%)
 Asian/Asian American12 (12%)
 Hispanic/Latino4 (4%)
 African American1 (1%)
Physician rolea 
 Attending83 (81%)
 Fellow20 (19%)
Training 
 Only informal training74 (79%)
 Formal and informal training20 (21%)

Goals of ICP

When asked to rank the most important goals of the ICP, physicians reported that providing information so families can decide about study entry (49%; 50 of 103) and explaining the progression of the disease and its treatment options (32%; 33 of 103) are the 2 highest priorities. Fourteen of 103 physicians (14%) viewed protection of the rights of subjects as the most important goal, whereas only 3 (3%) ranked documenting the review of risks and benefits, and 2 (2%) selected protecting children from research-related risks as the most important goal. Those who selected explaining progression of disease as the most important goal were more likely to have received only informal IC training (P < .05) (Table 2). Female physicians were more likely than male physicians to believe that providing information so families can decide about study entry is the most important goal of the ICP (P < .029) (Table 3).

Table 2. Physician Self-Reported Opinions Regarding the ICP for Pediatric Phase 1 Trials Based on the Type of IC Training They Received
OutcomesInformal Training N=74Formal Training N=20P
  1. ICP indicates informed consent process; IC, informed consent.

No. 1 goal of ICP is:
To explain progression of the disease
 Yes38%15%≤.050
Effect of ICP on parents' feeling of control:
 More in control52%20%≤.004
 No effect on control32%30%
 Less in control16%50%
Table 3. Physician Self-Reported Opinions Regarding the ICP for Pediatric Phase 1 Trials Based on Gender
OutcomesMale N=51Female N=52P
  1. ICP indicates informed consent process.

Effect of ICP on parents' anxiety
 Less anxious38%14%.008
 Have no effect on parents' anxiety28%26%
 More anxious34%61%
Statement best describing approach to ICP
 I describe the phase 1 study without any attempt to influence their decision76%52%.052
 I tell families about the phase 1 study and suggest that other children will benefit from what we learn in the study20%40%
 I explain the progression of the disease and its treatment options and recommend that the child go on the study4%8%
Directiveness in recommending phase 1 study
 Nondirective59%38%.03
No. 1 goal of ICP is:
To provide information regarding study entry
 Yes38%60%.029
Mean percentage of parents who understand the meaning of toxicity at the time of study enrollment
 77.668.9.045

Approach to IC

We asked our respondents to endorse from a list of 4 choices the 1 statement that best describes the way they approach IC discussions. Most pediatric oncologists reported that they describe the phase 1 study without any attempt to influence parents' decisions (64%; 63 of 99). Approximately 30% (30 of 99) reported that they tell families about the phase 1 study and suggest that other children will benefit from what is learned in the study. Six of 99 (6%) endorsed the approach of recommending that the child go on the phase 1 study. No respondents selected the option in which they suggest that the child will benefit directly from participation. Further analysis revealed male physicians were more likely to report that they describe the phase 1 study without any attempt to influence parental decision making, whereas female physicians reported a tendency to suggest that other children will benefit from what is learned in the study (P < .052) (Table 3).

The instrument contained a 5-point Likert scale asking “How directive are you when you recommend a Phase 1 study?” with “very directive” as a 1 and “nondirective” as a 5 at the 2 poles of the scale. Approximately 48% (48 of 99) responded that they were nondirective, and an additional 39% (39 of 99) of physicians circled the midpoint on the scale. None of the 99 respondents to this item circled the “very directive” response.

Physicians were asked to specify the youngest age at which a child should be included in a discussion about participation in phase 1 research. The mean age at which pediatric oncologists believed a child should be included in an IC discussion was 10 years (range, 3-16 years). Physicians were then asked to specify the youngest age at which a child should be involved in making a decision about participation in phase 1 research. The mean age at which pediatric oncologists reported a child should be involved in making a decision about participation in phase 1 research was 12 years (range, 5-18 years).

Therapeutic/Medical Benefit

When asked, “Do you believe that current patients receive direct therapeutic/medical benefit from participation in phase 1 studies?”, 58 of 96 physicians (60%) answered “yes” to this item, and the remaining 40% replied “no.” In the absence of a quantitative qualifier for this question, approximately 15% of the 58 answering “yes” to this question commented in the survey's margin that in reality only a small percentage of patients will directly benefit from phase 1 trial participation.

Perceived Parental Comprehension, Decision-Making, and Impact of the ICP

Parental comprehension of the rights of a research subject, design, and goals of a research trial are key endpoints for the ICP. In this study, we asked physicians to make percentage estimates of parents who understand a variety of concepts related to phase 1 research protocols at the time they decide whether to enroll their child on the study. On average, pediatric oncologists thought that approximately half of parents (51%; [standard deviation (SD), 24]) understand the term “dose escalation” and approximately 40% (SD, 23) of parents understand that their child will be unlikely to receive direct therapeutic/medical benefit from participating. Pediatric oncologists thought approximately three-quarters of parents understood the meaning of “toxicity” (73%; SD, 22); their right to withdraw from study (82%; SD, 20); that data collected about their child would be handled confidentially (81%; SD, 20); and they can choose other options for care, such as palliative treatment, comfort care, or hospice (73%; SD, 24).

When asked about who usually makes the decision about whether a young child (aged <14 years) with cancer enters a phase 1 study, physicians reported that parent(s) almost always (98%; 99 of 101 responses) make the decision. When asked about who usually makes this decision for an older child (aged >14 years) with cancer, 73% (74 of 102) still stated that the child's parent(s) makes the decision, whereas 26% of physicians believed the child himself/herself makes the decision about study entry.

When asked to assess the emotional impact of the phase 1 ICP on parents based on their observations, pediatric oncologists most often reported that the ICP usually makes parents feel more in control of the situation (45%; 46 of 101) but that the process makes parents feel more anxious (47%; 48 of 101).

Obstacles to Good IC

Respondents were asked to rank order a list of 5 possible obstacles to good IC. 12 The 2 answers most commonly chosen by physicians as the greatest obstacles to good IC were, “Parents' eagerness to ‘try anything’ after a recurrence/refractory diagnosis” (34%; 33 of 98) and “Maintaining hope for the parents/patient while providing accurate, honest information about the child's condition” (34%; 33 of 98). An additional 20% (20 of 98) of physicians reported that the greatest obstacle to good IC was the length of and language used in the consent document. The complexity of phase 1 study designs and requirements mandated by the Institutional Review Board were selected by only 10% and 3%, respectively.

Factors Associated With Physicians' Opinions

Our analyses indicated that physician gender and type of prior IC training may influence their approach to the ICP. For ease of comparison, Tables 2 and 3 itemize self-reported opinions of our subjects based on physician characteristics mentioned above.

Pediatric oncologists in this sample who had some formal consent training (P ≤ .004; Table 2), tended to report that the ICP usually makes parents feel more anxious and less in control of the situation. Similarly, female physicians (P ≤ .008; Table 3) believed parents are more likely to feel anxious after the ICP. More female (P ≤ .03; Table 3) physicians reported that they are directive when recommending a phase 1 study compared with their male counterparts.

Physicians' Suggestions

The survey's final open-ended question elicited suggestions from physicians about how to make the phase 1 ICP better. Of 103 physicians who completed surveys, 46 provided an answer to this question (response rate of 45%). Cumulative answers yielded a total of 63 suggestions, which were grouped into 8 different categories (Table 4). These 8 categories were further collapsed into 4 overriding themes: 1) issues with the overall ICP and document, 2) the role of physicians and other healthcare professionals (HCPs), 3) improvements in communication for families, and 4) other/regulatory issues.

Table 4. Categorization of Suggestionsa
CategoryFrequency (N=63)Percentage
  • ICP indicates informed consent process; HCPs, healthcare professionals.

  • a

    Suggestions from physicians to the question “How do you think we can make the phase 1 informed consent process better?”

Simplify consent content, length, and language1829
Formal physician training1016
Improve communication with parents/patients1016
Staged ICP914
Educational material for parents/patients610
Emphasize goals of trial46
Increase assistance from support HCPs46
Other23

The most frequently cited suggestion related to content of the IC document (29%). Twenty-eight percent of physician suggestions centered around roles of the pediatric oncologist and HCPs during the ICP. Approximately 16% suggested a formal training program focused on effective communication. Specific ways physicians suggested for improving communication included “spending more time” and “increasing transparency.”

Coders agreed that 2 open-ended responses did not fall into any category named above. These were considered in the other/regulatory category: 1 suggested a simplification of the study entry process, and the other pertained to the IRB's requirement to review the consent document verbatim as being problematic.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

We thank members of the POIC Research Team and all research staff and physicians who participated in this study. We acknowledge Ariane Mitchum for her assistance with assembly of data.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Supported by the National Institutes of Health (NIH) by means of the National Cancer Institute (NCI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (1RO1CA122217). Dr. Baker was supported in part by the American Lebanese Syrian Associated Charities (ALSAC). Dr. Rheingold received research funding from the Leukemia and Lymphoma Society for a Translational Research Grant (for a phase 1 drug trial).

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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